Azabenzothiazole compounds, compositions and methods of use

ABSTRACT

Provided are compounds of Formula I, stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, wherein A, X, R 1 , R 2 , R 4  and R 5  are defined herein, a pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, methods of using the compound or composition in therapy, and methods of manufacturing a compound of Formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application filed under 37 CFR §1.53(b) is acontinuation of U.S. application Ser. No. 13/232,778, filed on 14 Sep.2011, and also claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application Ser. No. 61/383,273, filed Sep. 15, 2010, whichare incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a patient, and in particular to inhibitors of TYK2kinase useful for treating diseases mediated by TYK2 kinase.

BACKGROUND OF INVENTION

Cytokine pathways mediate a broad range of biological functions,including many aspects of inflammation and immunity Janus kinases (JAK),including JAK1, JAK2, JAK3 and TYK2 are cytoplasmic protein kinases thatassociate with type I and type II cytokine receptors and regulatecytokine signal transduction. Cytokine engagement with cognate receptorstriggers activation of receptor associated JAKs and this leads toJAK-mediated tyrosine phosphorylation of signal transducer and activatorof transcription (STAT) proteins and ultimately transcriptionalactivation of specific gene sets. JAK1, JAK2 and TYK2 exhibit broadpatterns of gene expression, while JAK3 expression is limited toleukocytes. Cytokine receptors are typically functional as heterodimers,and as a result, more than one type of JAK kinase is usually associatedwith cytokine receptor complexes. The specific JAKs associated withdifferent cytokine receptor complexes have been determined in many casesthrough genetic studies and corroborated by other experimental evidence.

JAK1 is functionally and physically associated with the type Iinterferon (e.g., IFNalpha), type II interferon (e.g., IFNgamma), IL-2and IL-6 cytokine receptor complexes. JAK1 knockout mice die perinatallydue to defects in LIF receptor signaling. Characterization of tissuesderived from JAK1 knockout mice demonstrated critical roles for thiskinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways. A humanizedmonoclonal antibody targeting the IL-6 pathway (Tocilizumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis.

Biochemical and genetic studies have shown an association between JAK2and single-chain (e.g., EPO), IL-3 and interferon gamma cytokinereceptor families. Consistent with this, JAK2 knockout mice die ofanemia. Kinase activating mutations in JAK2 (e.g., JAK2 V617F) areassociated with myeloproliferative disorders (MPDS) in humans.

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is critical for lymphoid celldevelopment and proliferation and mutations in JAK3 result in severecombined immunodeficiency (SCID). Based on its role in regulatinglymphocytes, JAK3 and JAK3-mediated pathways have been targeted forimmunosuppressive indications (e.g., transplantation rejection andrheumatoid arthritis).

TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6,IL-10, IL-12 and IL-23 cytokine receptor complexes. Consistent withthis, primary cells derived from a TYK2 deficient human are defective intype I interferon, IL-6, IL-10, IL-12 and IL-23 signaling. A fully humanmonoclonal antibody targeting the shared p40 subunit of the IL-12 andIl-23 cytokines (Ustekinumab) was recently approved by the EuropeanCommission for the treatment of moderate-to-severe plaque psoriasis. Inaddition, an antibody targeting the IL-12 and IL-23 pathways underwentclinical trials for treating Crohn's Disease.

SUMMARY OF INVENTION

One embodiment includes a compound of Formula I:

and stereoisomers, tautomers, solvates, prodrugs and pharmaceuticallyacceptable salts thereof, wherein A, X, R¹, R², R⁴ and R⁵ are definedherein.

Another embodiment includes a pharmaceutical composition that includes acompound of Formula I, stereoisomers, tautomers, solvates, prodrugs orpharmaceutically acceptable salts thereof, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle.

Another embodiment includes a method of inhibiting TYK2 kinase activityin a cell, comprising introducing into said cell an amount effective toinhibit said kinase of a compound of Formula I, stereoisomers,tautomers, solvates, prodrugs or pharmaceutically acceptable saltsthereof.

Another embodiment includes a method of treating or lessening theseverity of a disease or condition responsive to the inhibition of TYK2kinase activity in a patient. The method includes administering to thepatient a therapeutically effective amount of a compound of Formula I,stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof.

Another embodiment includes use of a compound of Formula I,stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof, in therapy.

Another embodiment includes use of a compound of Formula I,stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof, in the treatment of an immunological orinflammatory disease.

Another embodiment includes use of a compound of Formula I,stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof, in manufacturing a medicament for treating adisease responsive to the inhibition of TYK2 kinase.

Another embodiment includes methods of preparing a compound of FormulaI, stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof.

Another embodiment includes a kit for treating a disease or disorderresponsive to the inhibition of TYK2 kinase. The kit includes a firstpharmaceutical composition comprising a compound of Formula I,stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof and instructions for use.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments, examples ofwhich are illustrated in the accompanying structures and formulas. Whilethe invention will be described in conjunction with the enumeratedembodiments, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims. One skilled in theart will recognize methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention.

DEFINITIONS

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted independently with one or more substituentsdescribed herein. In one example, the alkyl radical is one to eighteencarbon atoms (C₁-C₁₈). In other examples, the alkyl radical is C₀-C₆,C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, or C₁-C₃. C₀refers to a bond. Examples of alkyl groups include methyl (Me, —CH₃),ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl(i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon double bond, wherein the alkenyl radical may be optionallysubstituted independently with one or more substituents describedherein, and includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. In one example, the alkenylradical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, thealkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examplesinclude, but are not limited to, ethenyl or vinyl (—CH═CH₂), prop-1-enyl(—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl, but-1-enyl,but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon,triple bond, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein. In oneexample, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethynyl (—C≡CH),prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl, —CH₂C≡CH), but-1-ynyl,but-2-ynyl and but-3-ynyl.

“Alkylene” refers to a saturated, branched or straight chain hydrocarbongroup having two monovalent radical centers derived by the removal oftwo hydrogen atoms from the same or two different carbon atoms of aparent alkane. In one example, the divalent alkylene group is one toeighteen carbon atoms (C₁-C₁₈). C₀ refers to a bond. In other examples,the divalent alkylene group is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, or C₁-C₃. Example alkylene groups includemethylene (—CH₂—), 1,1-ethyl (—CH(CH₃)—), (1,2-ethyl (—CH₂CH₂—),1,1-propyl (—CH(CH₂CH₃)—), 2,2-propyl (—C(CH₃)₂—), 1,2-propyl(—CH(CH₃)CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,1-dimethyleth-1,2-yl(—C(CH₃)₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chainhydrocarbon group having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkene. In one example, the alkenylene group is two toeighteen carbon atoms (C₂-C₁₈). In other examples, the alkenylene groupis C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Example alkenylene groupsinclude: 1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chainhydrocarbon group having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkyne. In one example, the alkynylene radical is twoto eighteen carbon atoms (C₂-C₁₈). In other examples, the alkynyleneradical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Example alkynyleneradicals include: acetylene (—C≡C—), propargyl (—CH₂C≡C—), and4-pentynyl (—CH₂CH₂CH₂C≡C—).

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated hydrocarbon ring group wherein the cycloalkyl group may beoptionally substituted independently with one or more substituentsdescribed herein. In one example, the cycloalkyl group is 3 to 12 carbonatoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₈, C₃-C₁₀ orC₅-C₁₀. In other examples, the cycloalkyl group, as a monocycle, isC₃-C₄, C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as abicycle, is C₇-C₁₂. Examples of monocyclic cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atomsinclude, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6]ring systems. Exemplary bridged bicyclic cycloalkyls include, but arenot limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. In another example, the cycloalkyl, as a spiro, isC₅-C₁₂. Examples of spiro cycloalkyl include, but are not limited to,spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane,spiro[2.5]octane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane,spiro[4.4]nonane and spiro[4.5]decane.

“Aryl” refers to a cyclic aromatic hydrocarbon group optionallysubstituted independently with one or more substituents describedherein. In one example, the aryl group is 6-20 carbon atoms (C₆-C₂₀). Inanother example, the aryl group is C₆-C₁₀. In another example, the arylgroup is a C₆ aryl group. Aryl includes bicyclic groups comprising anaromatic ring with a fused non-aromatic or partially saturated ring.Example aryl groups include, but are not limited to, phenyl,naphthalenyl, anthracenyl, indenyl, indanyl, 1,2-dihydronapthalenyl and1,2,3,4-tetrahydronapthyl. In one example, aryl includes phenyl.Substituted phenyl or substituted aryl means a phenyl group or arylgroup substituted with one, two, three, four or five, for example 1-2,1-3 or 1-4 substituents chosen from groups specified herein. In oneexample, optional substituents on aryl are selected from halogen (F, Cl,Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for exampleC₁-C₆ alkyl), alkoxy (for example C₁-C₆ alkoxy), benzyloxy, carboxy,protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl, alkylsulfonylamino, alkyl sulfonylaminoalkyl, arylsulfonylamino, arylsulfonylamino alkyl,heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl,aryl, or other groups specified. One or more methyne (CH) and/ormethylene (CH₂) groups in these substituents may in turn be substitutedwith a similar group as those denoted above. Examples of the term“substituted phenyl” include a mono- or di(halo)phenyl group such as2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, theprotected-hydroxy derivatives thereof and the like; a nitrophenyl groupsuch as 3- or 4-nitrophenyl; a cyanophenyl group, for example,4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl,4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono ordi(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such 4-carboxyphenyl, a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenylgroups where the substituents are different, for example3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Particularsubstituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl,2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl,4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenylgroups. Fused aryl rings may also be substituted with any, for example1, 2 or 3, of the substituents specified herein in the same manner assubstituted alkyl groups.

“Halo” or “halogen” refer to F, Cl, Br or I.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to: (i) a saturated or partiallyunsaturated cyclic group (i.e., having one or more double and/or triplebonds within the ring) (“heterocycloalkyl”), or (ii) an aromatic cyclicgroup (“heteroaryl”), and in each case, which at least one ring atom isa heteroatom independently selected from nitrogen, oxygen, phosphorusand sulfur, the remaining ring atoms being carbon. The heterocyclylgroup may be optionally substituted with one or more substituentsdescribed below. In one embodiment, heterocyclyl includes monocycles orbicycles having 1 to 9 carbon ring members (C₁-C₉) with the remainingring atoms being heteroatoms selected from N, O, S and P. In otherexamples, heterocyclyl includes monocycles or bicycles having C₁-C₅,C₃-C₅ or C₄-C₅, with the remaining ring atoms being heteroatoms selectedfrom N, O, S and P. In another embodiment, heterocyclyl includes 3-10membered rings, 3-7-membered rings or 3-6 membered rings, containing oneor more heteroatoms independently selected from N, O, S and P. In otherexamples, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-memberedrings, containing one or more heteroatoms independently selected from N,O, S and P. In another embodiment, heterocyclyl includes bi- orpolycyclic, spiro or bridged 4-, 5-, 6-, 7-, 8- and 9-membered ringsystems, containing one or more heteroatoms independently selected fromN, O, S and P. Examples of bicycle systems include, but are not limitedto, [3,5], [4,5], [5,5], [3,6], [4,6], [5,6], or [6,6] systems. Examplesof bridged ring systems include, but are not limited to [2.2.1],[2.2.2], [3.2.2] and [4.1.0] arrangements, and having 1 to 3 heteroatomsselected from N, O, S and P. In another embodiment, heterocyclylincludes spiro groups having 1 to 4 heteroatoms selected from N, O, Sand P. The heterocyclyl group may be a carbon-linked group orheteroatom-linked group. “Heterocyclyl” includes a heterocyclyl groupfused to a cycloalkyl group.

Exemplary heterocyclyl groups include, but are not limited to, oxiranyl,aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl,1,3-dithietanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl,diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, imidazolidinyl,3-azabicyco[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl,6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl,3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl. Examples of aheterocyclyl group wherein a ring atom is substituted with oxo (═O) arepyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclyl groupsherein are optionally substituted independently with one or moresubstituents described herein. Heterocycles are described in Paquette,Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin,New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “TheChemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley& Sons, New York, 1950 to present), in particular Volumes 13, 14, 16,19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

The term “heteroaryl” refers to an aromatic carbocyclic radical in whichat least one ring atom is a heteroatom independently selected fromnitrogen, oxygen and sulfur, the remaining ring atoms being carbon.Heteroaryl groups may be optionally substituted with one or moresubstituents described herein. In one example, the heteroaryl groupcontains 1 to 9 carbon ring atoms (C₁-C₉). In other examples, theheteroaryl group is C₁-C₅, C₃-C₅ or C₄-C₅. In one embodiment, exemplaryheteroaryl groups include 5-6-membered rings, or monocyclic aromatic 5-,6- and 7-membered rings containing one or more heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In another embodiment,exemplary heteroaryl groups include fused ring systems of up to 9 carbonatoms wherein at least one aromatic ring contains one or moreheteroatoms independently selected from nitrogen, oxygen, and sulfur.“Heteroaryl” includes heteroaryl groups fused with an aryl, cycloalkylor other heterocyclyl group. Examples of heteroaryl groups include, butare not limited to, pyridinyl, imidazolyl, imidazopyridinyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, thiazolopyridinyl, and furopyridinyl.

In certain embodiments, the heterocyclyl or heteroaryl group isC-attached. By way of example and not limitation, carbon bondedheterocyclyls include bonding arrangements at position 2, 3, 4, 5, or 6of a pyridine (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl),position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of apyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline.

In certain embodiments, the heterocyclyl or heteroaryl group isN-attached. By way of example and not limitation, the nitrogen bondedheterocyclyl or heteroaryl group include bonding arrangements atposition 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline.

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,halogen atoms, hydroxyl, alkoxy (for example —OR, wherein R isindependently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl orheterocyclyl and R is independently optionally substituted) andsulfonyloxy (for example —OS(O)₁₋₂R, wherein R is independently alkyl,alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R isindependently optionally substituted) groups. Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)).

“Treat” and “treatment” includes both therapeutic treatment andprophylactic or preventative measures, wherein the object is to preventor slow down (lessen) an undesired physiological change or disorder,such as the development or spread of cancer. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, alleviation of symptoms, diminishment of extent of disease,stabilized (i.e., not worsening) state of disease, delay or slowing ofdisease progression, amelioration or palliation of the disease state,remission (whether partial or total), whether detectable orundetectable, sustaining remission and suppressing reoccurrence.“Treatment” can also mean prolonging survival as compared to expectedsurvival if not receiving treatment. Those in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a geneticmutation) or those in which the condition or disorder is to beprevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition or disorder, (ii) attenuates, amelioratesor eliminates one or more symptoms of the particular disease, condition,or disorder, or (iii) prevents or delays the onset of one or moresymptoms of the particular disease, condition or disorder describedherein. In the case of cancer, the therapeutically effective amount ofthe drug may reduce the number of cancer cells; reduce the tumor size;inhibit (i.e., slow to some extent and alternatively stop) cancer cellinfiltration into peripheral organs; inhibit (i.e., slow to some extentand alternatively stop) tumor metastasis; inhibit, to some extent, tumorgrowth; and/or relieve to some extent one or more of the symptomsassociated with the cancer. To the extent the drug may prevent growthand/or kill existing cancer cells, it may be cytostatic and/orcytotoxic. For cancer therapy, efficacy can, for example, be measured byassessing the time to disease progression (TTP) and/or determining theresponse rate (RR). In the case of immunological disorders, thetherapeutic effective amount is an amount sufficient to decrease oralleviate an allergic disorder, the symptoms of an autoimmune and/orinflammatory disease, or the symptoms of an acute inflammatory reaction(e.g. asthma). In some embodiments, a therapeutically effective amountis an amount of a chemical entity described herein sufficient tosignificantly decrease the activity or number of B-cells.

The term “NSAID” is an acronym for “non-steroidal anti-inflammatorydrug” and is a therapeutic agent with analgesic, antipyretic (loweringan elevated body temperature and relieving pain without impairingconsciousness) and, in higher doses, with anti-inflammatory effects(reducing inflammation). The term “non-steroidal” is used to distinguishthese drugs from steroids, which (among a broad range of other effects)have a similar eicosanoid-depressing, anti-inflammatory action. Asanalgesics, NSAIDs are unusual in that they are non-narcotic. NSAIDsinclude aspirin, ibuprofen, and naproxen. NSAIDs are usually indicatedfor the treatment of acute or chronic conditions where pain andinflammation are present. NSAIDs are generally indicated for thesymptomatic relief of the following conditions: rheumatoid arthritis,osteoarthritis, inflammatory arthropathies (e.g. ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, and renal colic. Most NSAIDs act as non-selective inhibitors ofthe enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1)and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes theformation of prostaglandins and thromboxane from arachidonic acid(itself derived from the cellular phospholipid bilayer by phospholipaseA₂). Prostaglandins act (among other things) as messenger molecules inthe process of inflammation. COX-2 inhibitors include celecoxib,etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, andvaldecoxib.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in patients that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, as well as head and neck cancer.

A “chemotherapeutic agent” is an agent useful in the treatment of agiven disorder, for example, cancer or inflammatory disorders. Examplesof chemotherapeutic agents include NSAIDs; hormones such asglucocorticoids; corticosteroids such as hydrocortisone, hydrocortisoneacetate, cortisone acetate, tixocortol pivalate, prednisolone,methylprednisolone, prednisone, triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodiumphosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasonedipropionate, betamethasone valerate, betamethasone dipropionate,prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,fluocortolone caproate, fluocortolone pivalate and fluprednideneacetate; immune selective anti-inflammatory peptides (ImSAIDs) such asphenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG)(IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such asazathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts,hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline,sulfasalazine, cyclophosphamide, tumor necrosis factor alpha (TNFα)blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab(Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin1 (IL-1) blockers such as anakinra (Kineret), monoclonal antibodiesagainst B cells such as rituximab (RITUXAN®), T cell costimulationblockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers suchas tocilizumab; hormone antagonists, such as tamoxifen, finasteride orLHRH antagonists; radioactive isotopes (e.g., At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰,R¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu);miscellaneous investigational agents such as thioplatin, PS-341,phenylbutyrate, ET-18-OCH₃, or farnesyl transferase inhibitors(L-739749, L-744832); polyphenols such as quercetin, resveratrol,piceatannol, epigallocatechine gallate, theaflavins, flavanols,procyanidins, betulinic acid and derivatives thereof; autophagyinhibitors such as chloroquine; alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol(dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; a camptothecin (including the synthetic analogue topotecan(HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin,scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); podophyllotoxin; podophyllinic acid; teniposide;cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogues, KW-2189 andCB1-TM1); eleutherobin; p ancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gamma1I and calicheamicinomegaI1 (see, e.g., Nicolaou et al., Angew. Chem. Intl. Ed. Engl., 33:183-186 (1994)); CDP323, an oral alpha-4 integrin inhibitor; dynemicin,including dynemicin A; an esperamicin; as well as neocarzinostatinchromophore and related chromoprotein enediyne antibiotic chromophores),aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins,dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HClliposome injection (DOXIL®), liposomal doxorubicin TLC D-99 (MYOCET®),peglylated liposomal doxorubicin (CAELYX®), and deoxydoxorubicin),epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such asmitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;anti-metabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur(UFTORAL®), capecitabine (XELODA®), an epothilone, and 5-fluorouracil(5-FU); folic acid analogues such as denopterin, methotrexate,pteropterin, trimetrexate; purine analogs such as fludarabine,6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such asancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens suchas calusterone, dromostanolone propionate, epitiostanol, mepitiostane,testolactone; anti-adrenals such as aminoglutethimide, mitotane,trilostane; folic acid replenisher such as frolinic acid; aceglatone;aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS NaturalProducts, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium;tenuazonic acid; triaziquone; 2,2′,2′-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verracurin A, roridin A andanguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); thiotepa; taxoid, e.g., paclitaxel (TAXOL®),albumin-engineered nanoparticle formulation of paclitaxel (ABRAXANE™),and docetaxel (TAXOTERE®); chloranbucil; 6-thioguanine; mercaptopurine;methotrexate; platinum agents such as cisplatin, oxaliplatin (e.g.,ELOXATIN®), and carboplatin; vincas, which prevent tubulinpolymerization from forming microtubules, including vinblastine(VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®, FILDESIN®), andvinorelbine (NAVELBINE®); etoposide (VP-16); ifosfamide; mitoxantrone;leucovorin; novantrone; edatrexate; daunomycin; aminopterin;ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine(DMFO); retinoids such as fenretinide, retinoic acid, includingbexarotene (TARGRETINO); bisphosphonates such as clodronate (forexample, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095,zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®),pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®);troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisenseoligonucleotides, particularly those that inhibit expression of genes insignaling pathways implicated in aberrant cell proliferation, such as,for example, PKC-alpha, Raf, H—Ras, and epidermal growth factor receptor(EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines,for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID®vaccine; topoisomerase 1 inhibitor (e.g., LURTOTECAN®); rmRH (e.g.,ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®,Pfizer); perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib),proteosome inhibitor (e.g. PS341); bortezomib (VELCADE®); CCI-779;tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such asoblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors (seedefinition below); farnesyltransferase inhibitors such as lonafarnib(SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids orderivatives of any of the above; as well as combinations of two or moreof the above such as CHOP, an abbreviation for a combined therapy ofcyclophosphamide, doxorubicin, vincristine, and prednisolone; andFOLFOX, an abbreviation for a treatment regimen with oxaliplatin(ELOXATIN™) combined with 5-FU and leucovorin.

Additional chemotherapeutic agents as defined herein include“anti-hormonal agents” or “endocrine therapeutics” which act toregulate, reduce, block, or inhibit the effects of hormones that canpromote the growth of cancer. They may be hormones themselves,including, but not limited to: anti-estrogens with mixedagonist/antagonist profile, including, tamoxifen (NOLVADEX®),4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene,raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogenreceptor modulators (SERMs) such as SERM3; pure anti-estrogens withoutagonist properties, such as fulvestrant (FASLODEX®), and EM800 (suchagents may block estrogen receptor (ER) dimerization, inhibit DNAbinding, increase ER turnover, and/or suppress ER levels); aromataseinhibitors, including steroidal aromatase inhibitors such as formestaneand exemestane (AROMASIN®), and nonsteroidal aromatase inhibitors suchas anastrazole (ARIMIDEX®), letrozole (FEMARA®) and aminoglutethimide,and other aromatase inhibitors include vorozole (RIVISOR®), megestrolacetate (MEGASE®), fadrozole, and 4(5)-imidazoles; lutenizinghormone-releaseing hormone agonists, including leuprolide (LUPRON® andELIGARD®), goserelin, buserelin, and tripterelin; sex steroids,including progestines such as megestrol acetate and medroxyprogesteroneacetate, estrogens such as diethylstilbestrol and premarin, andandrogens/retinoids such as fluoxymesterone, all transretionic acid andfenretinide; onapristone; anti-progesterones; estrogen receptordown-regulators (ERDs); anti-androgens such as flutamide, nilutamide andbicalutamide.

Additional chemotherapeutic agents include therapeutic antibodies suchas alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab(ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab(RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4,Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar,Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin(MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies withtherapeutic potential as agents in combination with the compounds of theinvention include: apolizumab, aselizumab, atlizumab, bapineuzumab,bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumabpegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab,epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin,inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab,mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab,nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab,pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab,ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab,ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumabtetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab,toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, ustekinumab, visilizumab, and the anti interleukin-12(ABT-874/J695, Wyeth Research and Abbott Laboratories) which is arecombinant exclusively human-sequence, full-length IgG₁ λ antibodygenetically modified to recognize interleukin-12 p40 protein.

Chemotherapeutic agents also include “EGFR inhibitors,” which refers tocompounds that bind to or otherwise interact directly with EGFR andprevent or reduce its signaling activity, and is alternatively referredto as an “EGFR antagonist.” Examples of such agents include antibodiesand small molecules that bind to EGFR. Examples of antibodies which bindto EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507),MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targetedantibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat.No. 5,212,290); humanized and chimeric antibodies that bind EGFR asdescribed in U.S. Pat. No. 5,891,996; and human antibodies that bindEGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen);EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996));EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR thatcompetes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); humanEGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known asE1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described inU.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanizedmAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Theanti-EGFR antibody may be conjugated with a cytotoxic agent, thusgenerating an immunoconjugate (see, e.g., EP659,439A2, Merck PatentGmbH). EGFR antagonists include small molecules such as compoundsdescribed in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307,5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726,6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, aswell as the following PCT publications: WO98/14451, WO98/50038,WO99/09016, and WO99/24037. Particular small molecule EGFR antagonistsinclude OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSIPharmaceuticals); PD 183805 (CI-1033, 2-propenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morph° linyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib(IRESSA™) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine,Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 orN-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6 [5[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors”including the EGFR-targeted drugs noted in the preceding paragraph;small molecule HER2 tyrosine kinase inhibitor such as TAK165 availablefrom Takeda; CP-724,714, an oral selective inhibitor of the ErbB2receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such asEKB-569 (available from Wyeth) which preferentially binds EGFR butinhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016;available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinaseinhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such ascanertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisenseagent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1signaling; non-HER targeted TK inhibitors such as imatinib mesylate(GLEEVEC™, available from Glaxo SmithKline); multi-targeted tyrosinekinase inhibitors such as sunitinib (SUTENT®, available from Pfizer);VEGF receptor tyrosine kinase inhibitors such as vatalanib(PTK787/ZK222584, available from Novartis/Schering AG); MAPKextracellular regulated kinase I inhibitor CI-1040 (available fromPharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines,such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines,4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; curcumin (diferuloylmethane, 4,5-bis(4-fluoro anilino)phthalimide); tyrphostines containingnitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules(e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S.Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474(Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors suchas CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinibmesylate (GLEEVEC™); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474(AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone),rapamycin (sirolimus, RAPAMUNE®); or as described in any of thefollowing patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016(American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983(Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (WarnerLambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include asthma treatment agents, includinginhaled corticosteroids such as fluticasone, budesonide, mometasone,flunisolide and beclomethasone; leukotriene modifiers, such asmontelukast, zafirlukast and zileuton; long-acting beta agonists, suchas salmeterol and formoterol; combinations of the above such ascombinations of fluticasone and salmeterol, and combinations ofbudesonide and formoterol; theophylline; short-acting beta agonists,such as albuterol, levalbuterol and pirbuterol; ipratropium; oral andintravenous corticosteroids, such as prednisone and methylprednisone;omalizumab; lebrikizumab; antihistamines; and decongestants; cromolyn;and ipratropium.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g. 0, 1, 2, 3 or4) of the substituents listed for that group in which said substituentsmay be the same or different. In an embodiment an optionally substitutedgroup has 1 substituent. In another embodiment an optionally substitutedgroup has 2 substituents. In another embodiment an optionallysubstituted group has 3 substituents.

The term “prodrug” as used in this application refers to a precursor orderivative form of a pharmaceutically active substance that is lessefficacious to the patient or cytotoxic to tumor cells compared to theparent drug and is capable of being enzymatically or hydrolyticallyactivated or converted into the more active parent form. See, e.g.,Wilman, “Prodrugs in Cancer Chemotherapy” Biochemical SocietyTransactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stellaet al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery,”Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, HumanaPress (1985). The prodrugs of this invention include, but are notlimited to, phosphate-containing prodrugs, thiophosphate-containingprodrugs, sulfate-containing prodrugs, peptide-containing prodrugs,D-amino acid-modified prodrugs, glycosylated prodrugs,β-lactam-containing prodrugs, optionally substitutedphenoxyacetamide-containing prodrugs or optionally substitutedphenylacetamide-containing prodrugs, 5-fluorocytosine and other5-fluorouridine prodrugs which can be converted into the more activecytotoxic free drug. Examples of cytotoxic drugs that can be derivatizedinto a prodrug form for use in this invention include, but are notlimited to, those chemotherapeutic agents described above.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space. Stereoisomers include diastereomers,enantiomers, conformers and the like.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and 1 or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or 1 meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofFormula I. “Pharmaceutically acceptable salts” include both acid andbase addition salts. Exemplary salts include, but are not limited, tosulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counter ion.The counter ion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counter ions. Hence, apharmaceutically acceptable salt can have one or more charged atomsand/or one or more counter ion, for example a dihydrochloride ordiformate salt.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of Formula I. Examples of solvents that formsolvates include, but are not limited to, water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term“hydrate” refers to the complex where the solvent molecule is water.

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable hydroxy-protecting groupsinclude acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, benzyl,benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, andtetrahydropyranyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene and P.Wuts, Protective Groups in Organic Synthesis, Third Ed., John Wiley &Sons, New York, 1999; and P. Kocienski, Protecting Groups, Third Ed.,Verlag, 2003.

The term “patient” includes human patients and animal patients. The term“animal” includes companion animals (e.g., dogs, cats and horses),food-source animals, zoo animals, marine animals, birds and othersimilar animal species. In one example, patient is a human.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “compound of this invention,” and “compounds of the presentinvention”, unless otherwise indicated, include compounds of Formulas I,stereoisomers, tautomers, solvates, prodrugs and salts (e.g.,pharmaceutically acceptable salts) thereof. Unless otherwise stated,structures depicted herein are also meant to include compounds thatdiffer only in the presence of one or more isotopically enriched atoms.For example, compounds of Formula I, wherein one or more hydrogen atomsare replaced deuterium or tritium, or one or more carbon atoms arereplaced by a ¹³C or ¹⁴C carbon atom, or one or more nitrogen atoms arereplaced by a ¹⁵N nitrogen atom, or one or more sulfur atoms arereplaced by a ³³S, ³⁴S or ³⁶S sulfur atom, or one or more oxygen atomsare replaced by a ¹⁷O or ¹⁸O oxygen atom are within the scope of thisinvention.

TYK2 Inhibitor Compounds

In one embodiment, a compound of Formulas I, stereoisomers, tautomers,solvates, prodrugs and pharmaceutically acceptable salts thereof, andpharmaceutical formulations thereof, are provided that are useful in thetreatment of diseases, conditions and/or disorders responsive to theinhibition of TYK2.

Another embodiment includes compounds of Formula I:

stereoisomers, tautomers, solvates, prodrugs and pharmaceuticallyacceptable salts thereof, wherein:

-   -   A is CR³ or N;    -   X is CR¹⁵ or N;    -   R¹ is independently hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —CF₃, —OR⁶, —SR⁶,        —OCF₃, —CN, —NO₂, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁶R⁷, —S(O)₁₋₂R⁶,        —S(O)₁₋₂NR⁶R⁷, —NR⁶S(O)₁₋₂R⁷, —NR⁶SO₂NR⁶R⁷, —NR⁶C(O)R⁷,        —NR⁶C(O)OR⁷, —NR⁶C(O)NR⁶R⁷, —OC(O)NR⁶R⁷ or —NR⁶R⁷, wherein both        R¹ cannot be hydrogen at the same time, and wherein said alkyl,        alkenyl, alkynyl and cycloalkyl are optionally substituted by        halogen, oxo, —CN, OR⁶, —NR⁶R⁷, C₃-C₆ cycloalkyl, 3-6 membered        heterocyclyl or phenyl and said cycloalkyl, heterocyclyl and        phenyl are independently optionally substituted by R¹⁰;    -   R² and R³ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃        alkylene)OR⁸, —(C₀-C₃ alkylene)SR⁸, —(C₀-C₃ alkylene)NR⁸R⁹,        —(C₀-C₃ alkylene)CF₃, —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃        alkylene)NO₂, —(C₀-C₃ alkylene)C(O)R⁸, —(C₀-C₃ alkylene)C(O)OR⁸,        —(C₀-C₃ alkylene)C(O)NR⁸R⁹, —(C₀-C₃ alkylene)NR⁸C(O)R⁹, —(C₀-C₃        alkylene)S(O)₁₋₂R⁸, —(C₀-C₃ alkylene)NR⁸S(O)₁₋₂R⁹, —(C₀-C₃        alkylene)S(O)₁₋₂NR⁸R⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl),        —(C₀-C₃ alkylene)(3-10-membered heterocyclyl), —(C₀-C₃        alkylene)(5-10-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,        wherein R² and R³ are each independently optionally substituted        by R¹⁰;    -   R⁴ is hydrogen, —NR⁶—, —NR⁶R⁷, —NR⁶C(O)—, —NR⁶C(O)O—,        —NR⁶C(O)NR⁷—, —NR⁶S(O)₁₋₂— or —NR⁶S(O)₁₋₂NR⁷—;    -   R⁵ is absent, hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 3-10-membered        heterocyclyl or 5-10-membered heteroaryl, wherein R⁵ is        optionally substituted by R¹⁰;    -   R⁶ and R⁷ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl or C₃-C₆ cycloalkyl, wherein said alkyl,        alkenyl, alkynyl and cycloalkyl are independently optionally        substituted by halogen, C₁-C₆ alkyl, oxo, CN, OR¹¹ or —NR¹¹R¹²;        or    -   R⁶ and R⁷ are independently taken together with the atom to        which they are attached to form a 3-6 membered heterocyclyl        optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹² or C₁-C₆        alkyl optionally substituted by halogen;    -   R⁸ and R⁹ are each independently hydrogen, C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, 3-6-membered heterocyclyl or 5-6-membered        heteroaryl, wherein said alkyl, cycloalkyl, phenyl, heterocyclyl        or heteroaryl are independently optionally substituted by R¹⁰;        or    -   R⁸ and R⁹ are independently taken together with the atom to        which they are attached to form a 3-6 membered heterocyclyl        optionally substituted by halogen, oxo, —NR¹¹R¹² or C₁-C₆ alkyl;

R¹⁰ is independently hydrogen, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹¹, —(C₀-C₃alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹², —(C₀-C₃ alkylene)CF₃, —(C₀-C₃alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃ alkylene)C(O)R¹¹, —(C₀-C₃alkylene)C(O)OR¹¹, —(C₀-C₃ alkylene)C(O)NR¹¹R¹², —(C₀-C₃alkylene)NR¹¹C(O)R¹², —(C₀-C₃ alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃ alkylene) S(O)₁₋₂NR¹¹R¹², —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)C(O)(3-10-membered heterocyclyl),—(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,wherein R¹⁰ is independently optionally substituted by halogen, oxo,—CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃ alkylene)NR¹³R¹⁴, —(C₀-C₃alkylene)C(O)R¹³, —(C₀-C₃ alkylene)S(O)₁₋₂R¹³ or C₁-C₆ alkyl optionallysubstituted by oxo, CN or halogen;

-   -   R¹¹ and R¹² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl or 3-6 membered heterocyclyl, wherein said alkyl,        alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and        heterocyclyl are independently optionally substituted by        halogen, oxo, —CN, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally        substituted by halogen, —CN or oxo; or    -   R¹¹ and R¹² are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl        optionally substituted by halogen, oxo or OH;    -   R¹³ and R¹⁴ are each independently hydrogen or C₁-C₆ alkyl        optionally substituted by halogen or oxo; or    -   R¹³ and R¹⁴ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by halogen or oxo;    -   R¹⁵ is hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹⁸, —(C₀-C₃        alkylene)SR¹⁸, —(C₀-C₃ alkylene)NR¹⁸R¹⁹, —(C₀-C₃ alkylene)CF₃,        —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —(C₀-C₃        alkylene)C(O)R¹⁹, —(C₀-C₃ alkylene)C(O)OR¹⁸, —(C₀-C₃        alkylene)C(O)NR¹¹R¹⁹, —(C₀-C₃ alkylene)NR¹⁸C(O)R¹⁹, —(C₀-C₃        alkylene)S(O)₁₋₂R¹⁸, —(C₀-C₃ alkylene)NR¹⁸S(O)₁₋₂R¹⁹, —(C₀-C₃        alkylene)S(O)₁₋₂NR¹⁸R¹⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl),        —(C₀-C₃ alkylene)(3-6-membered heterocyclyl), —(C₀-C₃        alkylene)(5-6-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl;    -   R¹⁶ and R¹⁷ are each independently hydrogen or C₁-C₆ alkyl        optionally substituted by halogen or oxo; or    -   R¹⁶ and R¹⁷ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by oxo or halogen; and    -   R¹⁸ and R¹⁹ are each independently hydrogen or C₁-C₆ alkyl        optionally substituted by halogen or oxo.

Another embodiment includes compounds of Formula I, stereoisomers,tautomers, solvates, prodrugs and pharmaceutically acceptable saltsthereof, wherein:

-   -   A is CR³ or N;    -   X is CR¹⁵ or N;    -   R¹ is independently hydrogen, halogen, C₁-C₃ alkyl, C₂-C₃        alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, —CF₃, —OR⁶, —SR⁶,        —OCF₃, —CN, —NO₂, —NR⁶SO₂R⁷, —NR⁶C(O)R⁷ or —NR⁶R⁷, wherein both        R¹ cannot be hydrogen at the same time, and wherein said alkyl,        alkenyl, alkynyl and cycloalkyl are optionally substituted by        halogen, OR⁶, —NR⁶R⁷ or phenyl;    -   R² and R³ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃        alkylene)OR⁸, —(C₀-C₃ alkylene)SR⁸, —(C₀-C₃ alkylene)NR⁸R⁹,        —(C₀-C₃ alkylene)CF₃, —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃        alkylene)NO₂, —(C₀-C₃ alkylene)C(O)R⁸, —(C₀-C₃ alkylene)C(O)OR⁸,        —(C₀-C₃ alkylene)C(O)NR⁸R⁹, —(C₀-C₃ alkylene)NR⁸C(O)R⁹, —(C₀-C₃        alkylene)S(O)₁₋₂R⁸, —(C₀-C₃ alkylene)NR⁸S(O)₁₋₂R⁹, —(C₀-C₃        alkylene)S(O)₁₋₂NR⁸R⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkylene),        —(C₀-C₃ alkylene)(3-6-membered heterocyclyl), —(C₀-C₃        alkylene)(5-6-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,        wherein R² and R³ are each independently optionally substituted        by R¹⁰;    -   R⁴ is hydrogen, —NH₂, —NH—, —NR⁶R⁷, —NR⁶C(O)—, —NR⁶C(O)O—,        —NR⁶C(O)NR⁷—, —NR⁶S(O)₁₋₂— or —NR⁶S(O)₁₋₂NR⁷—;    -   R⁵ is absent, hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 3-10-membered        heterocyclyl or 5-10-membered heteroaryl, wherein R⁵ is        optionally substituted by R¹⁰;    -   R⁶ and R⁷ are each independently hydrogen, C₁-C₃ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl or C₃-C₄ cycloalkyl, wherein said alkyl,        alkenyl, alkynyl and cycloalkyl are independently optionally        substituted by halogen, oxo, —OR¹¹ or —NR¹¹R¹²; or    -   R⁶ and R⁷ are independently taken together with the atom to        which they are attached to form a 3-6 membered heterocyclyl        optionally substituted by halogen, oxo, —NR¹¹R¹² or C₁-C₃ alkyl;    -   R⁸ and R⁹ are each independently hydrogen, C₁-C₃ alkyl, C₃-C₆        cycloalkyl, phenyl, 3-6-membered heterocyclyl or 5-6-membered        heteroaryl, wherein said alkyl, cycloalkyl, phenyl, heterocyclyl        or heteroaryl are independently optionally substituted by R¹⁰;        or    -   R⁸ and R⁹ are independently taken together with the atom to        which they are attached to form a 3-6 membered heterocyclyl        optionally substituted by halogen, oxo, —NR¹¹R¹² or C₁-C₃ alkyl;    -   R¹⁰ is independently hydrogen, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃        alkylene)OR¹¹, —(C₀-C₃ alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹²,        —(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃        alkylene)C(O)R¹¹, —(C₀-C₃ alkylene)C(O)OR¹¹, —(C₀-C₃        alkylene)C(O)NR¹¹R¹², —(C₀-C₃ alkylene)NR¹¹C(O)R¹², —(C₀-C₃        alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃ alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃        alkylene)S(O)₁₋₂NR¹¹R¹², —(C₀-C₃ alkylene)(C₃-C₆ cycloalkylene),        —(C₀-C₃ alkylene)(3-6-membered heterocyclyl), —(C₀-C₃        alkylene)C(O)(3-6-membered heterocyclyl), —(C₀-C₃        alkylene)(5-6-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,        wherein R¹⁰ is independently optionally substituted by halogen,        oxo, —CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃ alkylene)NR¹³R¹⁴,        —(C₀-C₃ alkylene)C(O)R¹³, —(C₀-C₃ alkylene)S(O)₁₋₂R¹³ or C₁-C₃        alkyl optionally substituted by oxo or halogen;    -   R¹¹ and R¹² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl or 3-6 membered heterocyclyl, wherein said alkyl,        alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and        heterocyclyl are independently optionally substituted by        halogen, oxo, —CN, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₃ alkyl optionally        substituted by halogen or oxo; or    -   R¹¹ and R¹² are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₃ alkyl        optionally substituted by halogen, oxo or OH;    -   R¹³ and R¹⁴ are each independently hydrogen or C₁-C₆ alkyl        optionally substituted by halogen or oxo; or    -   R¹³ and R¹⁴ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₃ alkyl optionally        substituted by halogen or oxo;    -   R¹⁵ is hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹⁸, —(C₀-C₃        alkylene)SR¹⁸, —(C₀-C₃ alkylene)NR¹⁸R¹⁹, —(C₀-C₃ alkylene)CF₃,        —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —(C₀-C₃        alkylene)C(O)R¹⁸, —(C₀-C₃ alkylene)C(O)OR¹⁸, —(C₀-C₃        alkylene)C(O)NR¹⁸R¹⁹, —(C₀-C₃ alkylene)NR¹⁸C(O)R¹⁹, —(C₀-C₃        alkylene)S(O)₁₋₂R¹⁸, —(C₀-C₃ alkylene)NR¹⁸S(O)₁₋₂R¹⁹, —(C₀-C₃        alkylene)S(O)₁₋₂NR¹⁸R¹⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl),        —(C₀-C₃ alkylene)(3-6-membered heterocyclyl), —(C₀-C₃        alkylene)(5-6-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl;    -   R¹⁶ and R¹⁷ are each independently hydrogen or C₁-C₆ alkyl        optionally substituted by halogen or oxo; or    -   R¹⁶ and R¹⁷ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₃ alkyl optionally        substituted by halogen; and    -   R¹⁸ and R¹⁹ are each independently hydrogen or C₁-C₆ alkyl        optionally substituted by halogen or oxo.

In certain embodiments, compounds of Formula I, stereoisomers,tautomers, solvates, prodrugs and pharmaceutically acceptable saltsthereof, includes compounds other than the compounds2-(2-chlorophenyl)thiazolo[5,4-c]pyridine,2-(thiazolo[5,4-c]pyridin-2-yl)aniline,2-phenoxy-N-(2-thiazolo[5,4-c]pyridin-2-yl-phenyl)-propanamide,N-(2-thiazolo[5,4-c]pyridin-2-ylphenyl)-benzenepropanamide,2-(2-methylphenyl)-thiazolo[5,4-c]pyridine,2-[2-methoxy-4-(methylthio)phenyl]-thiazolo[5,4-c]pyridine and2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine.

In certain embodiments, A is CR³.

In certain embodiments, A is CR³ and X is CR¹⁵.

In certain embodiments, A is CR³ and X is N.

In certain embodiments, A is N.

In certain embodiments, A is N and X is CR¹⁵

In certain embodiments, A is N and X is N.

In certain embodiments, R¹ is independently halogen. In one embodiment,R¹ is independently F or Cl. In another embodiment, R¹ is Cl.

In certain embodiments, R¹ is independently halogen; and the group—R⁴-R⁵ is —NHR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵ or —NR⁶C(O)NR⁷R⁵, wherein R⁵ isother than hydrogen.

In certain embodiments, R¹ is independently halogen or —CN; and thegroup —R⁴-R⁵ is —NHR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵ or —NR⁶C(O)NR⁷R⁵.

In certain embodiments, one R¹ is halogen and the other R¹ is hydrogen,halogen, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH,—S(C₁-C₃ alkyl), —OCF₃, —CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷,wherein said alkyl and cycloalkyl are optionally substituted by halogen,OR⁸, —NR⁸R⁹ or phenyl.

In certain embodiments, one R¹ is halogen and the other R¹ is hydrogen,halogen, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH,—S(C₁-C₃ alkyl), —OCF₃, —CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷,wherein said alkyl and cycloalkyl are optionally substituted by halogen,OR⁶, —NR⁶R⁷ or phenyl.

In certain embodiments, one R¹ is halogen and the other R¹ is halogen,C₁-C₃ alkyl, C₃-C₄ cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH, —S(C₁-C₃alkyl), —OCF₃, —CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷, wherein saidalkyl and cycloalkyl are optionally substituted by halogen, OR⁸, —NR⁸R⁹or phenyl.

In certain embodiments, one R¹ is halogen and the other R¹ is halogen,C₁-C₃ alkyl, C₃-C₄ cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH, —S(C₁-C₃alkyl), —OCF₃, —CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷, wherein saidalkyl and cycloalkyl are optionally substituted by halogen, OR⁶, —NR⁶R⁷or phenyl.

In certain embodiments, R¹ is independently halogen, C₁-C₃ alkyl, C₃-C₄cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH, —S(C₁-C₃ alkyl), —OCF₃,—CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷, wherein said alkyl andcycloalkyl are optionally substituted by halogen, OR⁸, —NR⁸R⁹ or phenyl.

In certain embodiments, R¹ is independently halogen, C₁-C₃ alkyl, C₃-C₄cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH, —S(C₁-C₃ alkyl), —OCF₃,—CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷, wherein said alkyl andcycloalkyl are optionally substituted by halogen, OR⁶, —NR⁶R⁷ or phenyl.

In certain embodiments, R¹ is independently hydrogen, F, Cl, —CF₃, —CH₃,or —OCF₃, wherein both R¹ cannot be hydrogen at the same time.

In certain embodiments, R¹ is independently hydrogen, F, Cl or —CN,wherein both R¹ cannot be hydrogen at the same time.

In certain embodiments, R¹ is independently halogen or —CN. In certainembodiments, R¹ is independently F, Cl or —CN. In certain embodiments,one R¹ is halogen and the other R¹ is —CN.

In certain embodiments, R¹ is —CN.

In certain embodiments, R² is hydrogen or halogen.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —CN, —C(O)R⁸ or —S(O)₁₋₂(C₁-C₃ alkyl), whereinsaid alkyl, alkenyl and alkynyl are independently optionally substitutedby halogen, oxo, —OR⁸ or —NR⁸R⁹. In one embodiment, R³ is hydrogen,hydroxylmethyl, —C(O)H, ethenyl, —CN or —S(O)₂CH₃. In one embodiment, R³is hydrogen, —C(O)H, ethenyl, —CN or hydroxymethyl. In one embodiment,R³ is hydrogen. In one embodiment, R³ is —CN.

In certain embodiments, R³ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —CN, —C(O)R⁸ or —S(O)₁₋₂(C₁-C₃ alkyl), whereinsaid alkyl, alkenyl and alkynyl are independently optionally substitutedby halogen, oxo, —OR¹¹ or —NR¹¹R¹².

In certain embodiments, R³ is C₁-C₆ alkyl optionally substituted byhalogen, oxo, —OR⁸ or —NR⁸R⁹. In certain embodiments, R³ is —CH₂OH or—CH₂NH₂.

In certain embodiments, R³ is C₁-C₆ alkyl optionally substituted byhalogen, oxo, —OR¹¹ or —NR¹¹R¹².

In certain embodiments, R³ is 3-10 membered heterocyclyl optionallysubstituted by halogen, oxo, —OR¹¹, —NR¹¹R¹² or C₁-C₆ alkyl optionallysubstituted by halogen or oxo. In certain embodiments, R³ is aziridinyl.

In certain embodiments, R³ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —CN, —NR⁸R⁹, —NR⁸C(O)R⁹, —C(O)R⁸ or—S(O)₁₋₂(C₁-C₃ alkyl), wherein said alkyl, alkenyl and alkynyl areindependently optionally substituted by halogen, oxo, —OR¹¹ or —NR¹¹R¹².In one embodiment, R³ is hydrogen, hydroxylmethyl, —CH₂NH₂, aziridinyl,cyclopropyl, —C(O)NH₂, —NHC(O)CH₃, —OCH₃, —C(O)H, ethenyl, —CN or—S(O)₂CH₃.

In certain embodiments, A is CR³, R² is hydrogen and R³ is hydrogen, —CNor hydroxymethyl.

In certain embodiments, A is CR³, R² is hydrogen and R³ is hydrogen,—CN, —CH₂NH₂, —NHC(O)CH₃ or hydroxymethyl. In certain embodiments, A isCR³, R² is hydrogen and R³ is hydrogen or —CN. In certain embodiments,R¹ is independently halogen or —CN, A is CR³, R² is hydrogen and R³ ishydrogen or —CN,

In certain embodiments, the portion of Formula I having the structure:

is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, the portion of Formula I having the structure:

is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁴ is hydrogen and R⁵ is absent.

In certain embodiments, R¹ is independently hydrogen, halogen or —CN; R⁴is hydrogen and R⁵ is absent. In certain embodiments, R¹ isindependently halogen or —CN; R⁴ is hydrogen and R⁵ is absent.

In certain embodiments, R⁴ is —NR⁶—. In certain embodiments, R⁴ is—NR⁶C(O)—. In certain embodiments, R⁴ is —NR⁶C(O)O—. In certainembodiments, R⁴ is —NR⁶C(O)NR⁷—. In certain embodiments, R⁴ is —NH—. Incertain embodiments, R⁴ is —NHC(O)—. In certain embodiments, R⁴ is—NHC(O)O—. In certain embodiments, R⁴ is —NHC(O)NH—.

In certain embodiments, R⁴ is —NR⁶—, —NR⁶C(O)—, —NR⁶C(O)O— or—NR⁶C(O)NR⁷—.

In certain embodiments, the group —R⁴-R⁵ is —NHR⁵, —NHC(O)R⁵, —NHC(O)OR⁵or —NHC(O)NHR⁵.

In certain embodiments, the group —R⁴-R⁵ is —NHR⁵, —NHC(O)R⁵, —NHC(O)OR⁵or —NHC(O)NHR⁵, wherein R⁵ is other than hydrogen.

In certain embodiments, X is CR¹⁵ and the group —R⁴-R⁵ is —NHR⁵,—NHC(O)R⁵, —NHC(O)OR⁵ or —NHC(O)NR⁷R⁵. In certain embodiments, X isCR¹⁵; R¹⁵ is hydrogen; and the group —R⁴-R⁵ is —NHR⁵, —NHC(O)R⁵,—NHC(O)OR⁵ or —NHC(O)NHR⁵, wherein R⁵ is other than hydrogen. In certainembodiments, A is CR³; X is CR¹⁵; R¹⁵ is hydrogen; and the group —R⁴-R⁵is —NHR⁵, —NHC(O)R⁵, —NHC(O)OR⁵ or —NHC(O)NHR⁵, wherein R⁵ is other thanhydrogen.

In certain embodiments, X is CR¹⁵; R¹⁵ is hydrogen, halogen or —CN; andthe group —R⁴-R⁵ is —NHR⁵, —NHC(O)R⁵, —NHC(O)OR⁵ or —NHC(O)NHR⁵, whereinR⁵ is other than hydrogen. In certain embodiments, A is CR³; X is CR¹⁵;R¹⁵ is hydrogen, halogen or —CN; and the group —R⁴-R⁵ is —NHR⁵,—NHC(O)R⁵, —NHC(O)OR⁵ or —NHC(O)NHR⁵, wherein R⁵ is other than hydrogen.In certain embodiments, A is CR³; R¹ is independently halogen or —CN; Xis CR¹⁵; R¹⁵ is hydrogen, halogen or —CN; and the group —R⁴-R⁵ is —NHR⁵,—NHC(O)R⁵, —NHC(O)OR⁵ or —NHC(O)NHR⁵, wherein R⁵ is other than hydrogen.

In certain embodiments, R⁴ is —NH—, —NHC(O)— or —NHC(O)NH—.

In certain embodiments, R⁴ is —NH₂ and R⁵ absent.

In certain embodiments, R⁵ is hydrogen.

In certain embodiments, R⁴ is —NR⁶R⁷; R⁵ is absent; and R⁶ and R⁷ areindependently hydrogen, C₁-C₃ alkyl or C₃-C₄ cycloalkyl, wherein saidalkyl and cycloalkyl are independently optionally substituted byhalogen, oxo, —OR¹¹ or —NR¹¹R¹².

In certain embodiments, R⁵ is C₁-C₆ alkyl optionally substituted byhalogen, oxo, —OR¹¹, —SR¹¹, —CN, C₃-C₁₀ cycloalkyl, —C(O)R¹¹ or—NR¹¹R¹². In certain embodiments, R⁵ is C₁-C₆ alkyl optionallysubstituted by halogen, oxo, —OR¹¹, —SR¹¹, —C(O)R¹¹ or —NR¹¹R¹². Incertain embodiments, R⁵ is methyl, ethyl, isopropyl, tert-butyl, —CH₂OH,—CH₂NH₂, —CH₂N(CH₃)₂ or —CH₂CH₂NH₂. In certain embodiments, R⁵ ismethyl, ethyl, isopropyl, tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH₂CN,—CH₂NH₂, —CH₂N(CH₃)₂ or —CH₂CH₂NH₂.

In certain embodiments, R⁵ is C₃-C₁₀ cycloalkyl optionally substitutedby R¹⁰. In certain embodiments, R⁵ is C₃-C₆ cycloalkyl optionallysubstituted by halogen. In certain embodiments, R⁵ is cyclopropyloptionally substituted by halogen. In certain embodiments, R⁵ iscyclopropyl. In certain embodiments, R⁵ is selected from:

wherein the wavy line represents the point of attachment in Formula I.

In certain embodiments, R⁵ is cyclopropyl. In certain embodiments, R⁵ isselected from:

wherein the wavy line represents the point of attachment in Formula I.

In certain embodiments, R⁵ is C₆-C₁₀ aryl optionally substituted by R¹⁰.In certain embodiments, R⁵ is selected from phenyl, naphthalenyl,dihyrdoindenyl and tetrahydronaphthalenyl, wherein R⁵ is optionallysubstituted by R¹⁰.

In certain embodiments, R⁵ is phenyl optionally substituted by R¹⁰. Incertain embodiments, R⁵ is phenyl. In certain embodiments, R⁵ is phenyloptionally substituted by —O(CH₂)₂pyrrolidinyl.

In certain embodiments, R⁵ is 3-10-membered heterocyclyl optionallysubstituted by R¹⁰.

In certain embodiments, R⁵ is 3-7-membered heterocyclyl optionallysubstituted by R¹⁰.

In certain embodiments, R⁵ is 5-10-membered heteroaryl optionallysubstituted by R¹⁰. In certain embodiments, R⁵ is pyridinyl,pyrimidinyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl orisoxazolyl, wherein said R⁵ is optionally substituted by R¹⁰.

In certain embodiments, R⁵ is pyridinyl, pyrimidinyl, pyrazolyl,thiazolyl, pyrazinyl, pyridazinyl, oxazolyl or isoxazolyl optionallysubstituted by C₁-C₆ alkyl, halogen, —CN, —O(C₀-C₃ alkyl), —CF₃,—NR¹¹R¹², —C═NH(OR¹¹), —C(O)OR¹¹, 3-6-membered heterocyclyl, whereinsaid alkyl is optionally substituted by halogen or OR¹¹ and saidheterocyclyl is optionally substituted by oxo, halogen or C₁-C₃ alkyloptionally substituted by halogen or OR¹¹.

In certain embodiments, R⁵ is pyridinyl, pyrimidinyl, pyrazolyl,thiazolyl, pyrazinyl, pyridazinyl, oxazolyl or isoxazolyl optionallysubstituted by C₁-C₆ alkyl, halogen, —CN, —O(C₁-C₃ alkyl), —CF₃,—NR¹¹R¹², —C═NH(OR¹¹), —C(O)OR¹¹, 3-6-membered heterocyclyl, whereinsaid alkyl is optionally substituted by halogen or OR¹³ and saidheterocyclyl is optionally substituted by oxo, halogen or C₁-C₃ alkyloptionally substituted by halogen or OR¹³.

In certain embodiments, R⁵ is 5-6-membered heteroaryl, wherein R⁵ isoptionally substituted by R¹⁰, wherein R¹⁰ is C₁-C₆ alkyl, halogen, —CN,—OR¹¹, —SR¹¹, —NR¹¹R¹², —CF₃, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR¹¹R¹²,—NR¹¹C(O)R¹², —S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂R¹², —S(O)₁₋₂NR¹¹R¹², C₃-C₆cycloalkyl, 3-6-membered heterocyclyl, —C(O)(3-6-membered heterocyclyl),5-6-membered heteroaryl or phenyl, wherein R¹⁰ is independentlyoptionally substituted by halogen, C₁-C₃ alkyl, oxo, —CF₃, —OR¹³,—NR¹³R¹⁴, —C(O)R¹³ or —S(O)₁₋₂R¹³. In an example, R⁵ is pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, pyrazolyl,pyranyl, triazolyl, isoxazolyl, oxazolyl, imidazolyl, thiazolyl orthiadiazolyl, wherein R⁵ is optionally substituted by 1, 2 or 3 R¹⁰.

In certain embodiments, R⁵ is pyridinyl optionally substituted by C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN,—(C₀-C₃ alkylene)OR¹¹, —(C₀-C₃ alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹²,—(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃alkylene)C(O)R¹¹, —(C₀-C₃ alkylene)C(O)OR¹¹, —(C₀-C₃alkylene)C(O)NR¹¹R¹², —(C₀-C₃ alkylene)NR¹¹C(O)R¹², —(C₀-C₃alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃ alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃alkylene)S(O)₁₋₂NR¹¹R¹², —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)(3-6-membered heterocyclyl), —(C₀-C₃ alkylene)C(O)(3-6-memberedheterocyclyl), —(C₀-C₃ alkylene)(5-6-membered heteroaryl) or —(C₀-C₃alkylene)phenyl, wherein R¹⁰ is independently optionally substituted byhalogen, C₁-C₃ alkyl, oxo, —CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃alkylene)NR¹³R¹⁴, —(C₀-C₃ alkylene)C(O)R¹³ or —(C₀-C₃alkylene)S(O)₁₋₂R¹³.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁵ is pyrimidinyl, pyridazinyl, or pyrazinyl,optionally substituted by C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹¹, —(C₀-C₃alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹², —(C₀-C₃ alkylene)CF₃, —(C₀-C₃alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃ alkylene)C(O)R¹¹, —(C₀-C₃alkylene)C(O)OR¹¹, —(C₀-C₃ alkylene)C(O)NR¹¹R¹², —(C₀-C₃alkylene)NR¹¹C(O)R¹², —(C₀-C₃ alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃ alkylene)S(O)₁₋₂NR¹¹R¹², —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-6-memberedheterocyclyl), —(C₀-C₃ alkylene)C(O)(3-6-membered heterocyclyl), —(C₀-C₃alkylene)(5-6-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl, whereinR¹⁰ is independently optionally substituted by halogen, C₁-C₃ alkyl,oxo, —CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃ alkylene)NR¹³R¹⁴, —(C₀-C₃alkylene)C(O)R¹³ or —(C₀-C₃ alkylene)S(O)₁₋₂R¹³.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R⁵ is pyrimidinyl optionally substituted byC₁-C₃ alkyl and —NR¹¹R¹². In certain embodiments, R⁵ is pyrimidinyloptionally substituted by methyl and —NH₂.

In certain embodiments, R⁵ is pyrazolyl, isoxazolyl, oxazolyl,imidazolyl, thiazolyl or thiadiazolyl, wherein R⁵ is optionallysubstituted by R¹⁰, wherein R¹⁰ is C₁-C₆ alkyl, halogen, —CN, —OR¹¹,—SR¹¹, —NR¹¹R¹², —CF₃, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR¹¹R¹², —NR¹¹C(O)R¹²,—S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂R¹², —S(O)₁₋₂NR¹¹R¹², C₃-C₆ cycloalkyl,3-6-membered heterocyclyl, —C(O)(3-6-membered heterocyclyl),5-6-membered heteroaryl or phenyl, wherein R¹⁰ is independentlyoptionally substituted by halogen, C₁-C₃ alkyl, oxo, —CF₃, —OR¹³,—NR¹³R¹⁴, —C(O)R¹³ or —S(O)₁₋₂R¹³. In certain embodiments, R⁵ ispyrazolyl optionally substituted by R¹⁰.

In certain embodiments, R⁵ is selected from:

wherein the wavy lines represent the point of attachment in Formula I.

In certain embodiments, R¹⁰ is independently halogen. In certainembodiments, R¹⁰ is independently F.

In certain embodiments, R¹⁰ is independently —CN.

In certain embodiments, R¹⁰ is independently C₁-C₆ alkyl, C₂-C₆ alkenylor C₂-C₆ alkynyl, wherein said alkyl, alkenyl and alkynyl areindependently optionally substituted by halogen, oxo, —OR¹³ or —NR¹³R¹⁴.In certain embodiments, R¹⁰ is methyl, ethyl, isopropy, —CH₂OH,—CH₂CH₂OH, —CH(OH)CH₂OH, —C(CH₃)₂OH, —CH₂NH₂, —CH₂N(CH₃)₂, —CF₃,—C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂ or —C(O)morpholinyl. In certainembodiments, R¹⁰ is methyl.

In certain embodiments, R¹⁰ is independently C₁-C₆ alkyl, C₂-C₆ alkenylor C₂-C₆ alkynyl, wherein said alkyl, alkenyl and alkynyl areindependently optionally substituted by halogen, oxo, —OR¹³ or —NR¹³R¹⁴.In certain embodiments, R¹⁰ is methyl, ethyl, isopropy, —CH₂OH,—CH₂CH₂OH, —CH(OH)CH₂OH, —C(CH₃)₂OH, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—CF₃, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, —CH₂thiomorpholinyl dioxide,—CH₂-morpholinyl, (R)—CH(OH)CH₃, (R)—CH(NH₂)CH₃, (S)—CH(OH)CH₃,(S)—CH(NH₂)CH₃ or —C(O)morpholinyl. In certain embodiments, R¹⁰ ismethyl.

In certain embodiments, R¹⁰ is independently C₃-C₆ cycloalkyl optionallysubstituted by halogen, oxo or C₁-C₃ alkyl. In certain embodiments, R¹⁰is independently cyclopropyl.

In certain embodiments, R¹⁰ is independently 3-6 membered heterocyclylor —C(O)(3-6 membered heterocyclyl), wherein said heterocyclyl isindependently optionally substituted by —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃alkylene)NR¹³R¹⁴, halogen, —CN, oxo or C₁-C₆ alkyl optionallysubstituted by oxo or halogen. In certain embodiments, said heterocyclylis morpholinyl, thiomorpholinyl, piperizinyl, piperidinyl or aziridinyl,wherein said heterocyclyl is independently optionally substituted byoxo, —CH₂OH, —CH₂CH₂OH, —OH, methyl or —CF₃. In certain embodiments, R¹⁰is independently selected from:

wherein the wavy line represents the point of attachment in Formula I.

In certain embodiments, R¹⁰ is independently —(C₀-C₃ alkylene)OR¹¹ or—(C₀-C₃ alkylene)SR¹¹. In certain embodiments, R¹⁰ is —OH, —OCH₃,—CH₂OH, —CH₂CH₂OH, —CH(OH)CH₂OH or —C(CH₃)₂OH. In certain embodiments,R¹⁰ is —OH or —OCH₃. In certain embodiments, R¹⁰ is —OH, —OCH₃, —CH₂OH,—CH₂CH₂OH, —CH(OH)CH₂OH, —C(CH₃)₂OH. (R)—CH(OH)CH₃ or (S)—CH(OH)CH₃.

In certain embodiments, R¹⁰ is independently —(C₀-C₃ alkylene)NR¹¹R¹².In certain embodiments, R¹⁰ is —NH₂, —NHCH₃, —NHC(O)CH₃, —N(CH₃)₂,—N(CH₂CH₂OH)₂, —NHCH₂CH₂OH, —N(CH₃)CH₂CH₂OH, —NHCH₂C(CH₃)₂OH,—N(CH₃)CH₂C(CH₃)₂OH, 4-hydroxyaziridin-1-yl, morpholinyl,dioxothiomorpholinyl, piperidinyl, 4-hydroxypiperidinyl,4-methylpiperazinyl, pyrrolidinyl or 4-(2-hydroxyethyl)piperazinyl. Incertain embodiments, R¹⁰ is —NH₂, —NHCH₃, —NHC(O)CH₃, —N(CH₃)₂,—N(CH₂CH₂OH)₂, —NHCH₂CH₂OH, —N(CH₃)CH₂CH₂OH, —NHCH₂C(CH₃)₂OH,—N(CH₃)CH₂C(CH₃)₂OH, 4-hydroxyaziridin-1-yl, morpholinyl,dioxothiomorpholinyl, piperidinyl, 4-hydroxypiperidinyl,4-methylpiperazinyl, pyrrolidinyl, —CH₂thiomorpholinyl dioxide,—CH₂-morpholinyl, (R)—CH(NH₂)CH₃, (S)—CH(NH₂)CH₃ or4-(2-hydroxyethyl)piperazinyl.

In certain embodiments, R¹⁰ is independently —C(O)NR¹¹R¹². In certainembodiments, R¹⁰ is —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂ or—C(O)morpholinyl.

In certain embodiments, R¹⁰ is independently C₁-C₆ alkyl, halogen, —CN,—OR¹¹, —SR¹¹, —NR¹¹R¹², —CF₃, —C═NH(OR¹¹), —C(O)OR¹¹, C₃-C₆ cycloalkyl,3-6-membered heterocyclyl, 5-6-membered heteroaryl or phenyl, whereinR¹⁰ is independently optionally substituted by halogen, oxo, —CF₃,—OR¹³, —NR¹³R¹⁴, —C(O)R¹³, —S(O)₁₋₂R¹³ or C₁-C₃ alkyl optionallysubstituted by oxo or halogen.

In certain embodiments, R¹⁰ is independently selected from F, —CN,methyl, ethyl, isopropy, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₂OH, —C(CH₃)₂OH,—CH₂NH₂, —CH₂N(CH₃)₂, —CF₃, —OH, —OCH₃, —NH₂, —NHCH₃, —NHC(O)CH₃,—N(CH₃)₂, —N(CH₂CH₂OH)₂, —NHCH₂CH₂OH, —N(CH₃)CH₂CH₂OH, —NHCH₂C(CH₃)₂OH,—N(CH₃)CH₂C(CH₃)₂OH, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂,

wherein the wavy line represents the point of attachment in Formula I.

In certain embodiments, R¹⁰ is independently selected from F, —CN,methyl, ethyl, isopropy, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₂OH, —C(CH₃)₂OH,—CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —OH, —OCH₃, —NH₂, —NHCH₃,—NHC(O)CH₃, —N(CH₃)₂, —N(CH₂CH₂OH)₂, —NHCH₂CH₂OH, —N(CH₃)CH₂CH₂OH,—NHCH₂C(CH₃)₂OH, —N(CH₃)CH₂C(CH₃)₂OH, —C(O)NH₂, —C(O)NHCH₃,—C(O)N(CH₃)₂, —CH₂thiomorpholinyl dioxide, —CH₂morpholinyl,—CH₂cyclopropyl, —CH(OH)CH₃, —CH(NH₂)CH₃, (R)—CH(OH)CH₃, (R)—CH(NH₂)CH₃,(S)—CH(OH)CH₃, (S)—CH(NH₂)CH₃,

wherein the wavy line represents the point of attachment in Formula I.

In certain embodiments, R¹¹ and R¹² are independently hydrogen or C₁-C₆alkyl optionally substituted by halogen, oxo, —CN, —OR¹⁶ or —NR¹⁶R¹⁷, orare taken together with the atom to which they attached to form a 3-6membered heterocyclyl optionally substituted by halogen, oxo, —OR¹⁶,—NR¹⁶R¹⁷ or C₁-C₃ alkyl optionally substituted by halogen, oxo or OH.

In certain embodiments, R¹¹ and R¹² are independently hydrogen, methyl,—C(O)CH₃, 2-hydroxy-2-methylpropyl or 2-hydroxyethyl, or are takentogether with the atom to which they attached to form a azetidinyl,pyrrolidinyl, morpholinyl, dioxothiomorphlinyl, piperazinyl orpiperidinyl ring optionally substituted by halogen, oxo or C₁-C₃ alkyloptionally substituted by oxo, halogen or OH.

In certain embodiments, R¹¹ and R¹² are independently hydrogen, methyl,—C(O)CH₃, 2-hydroxy-2-methylpropyl or 2-hydroxyethyl.

In certain embodiments, R¹³ and R¹⁴ are independently hydrogen or C₁-C₃alkyl. In certain embodiments, R¹³ and R¹⁴ are independently hydrogen ormethyl.

In certain embodiments, R¹⁵ is hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —CN, —OR¹⁸, —SR¹⁸, —NR¹⁸R¹⁹, —CF₃, —OCF₃, —NO₂,—C(O)R¹⁸, —C(O)OR¹⁸, —C(O)NR¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹, —S(O)₁₋₂R¹⁸,—NR¹⁸S(O)₁₋₂R¹⁹, —S(O)₁₋₂NR¹⁸R¹⁹, —(C₃-C₆ cycloalkyl), -(3-6-memberedheterocyclyl), -(5-6-membered heteroaryl) or -phenyl.

In certain embodiments, R¹⁵ is hydrogen, halogen, —CF₃ or C₁-C₃ alkyl.In certain embodiments, R¹⁵ is methyl. In certain embodiments, R¹⁵ ishalogen. In certain embodiments, R¹⁵ is F.

In certain embodiments, R¹⁵ is —(C₀-C₃ alkylene)OR¹⁸. In certainembodiments, R¹⁵ is —CH₂OR¹⁸. In certain embodiments, R¹⁵ is —CH₂OH.

In certain embodiments, R¹⁵ is hydrogen, halogen, —CN, —CH₂OH, —CF₃ orC₁-C₃ alkyl. In certain embodiments, R¹⁵ is methyl. In certainembodiments, R¹⁵ is halogen. In certain embodiments, R¹⁵ is F or Br. Incertain embodiments, R¹⁵ is F, Br, CN or CH₂OH.

In certain embodiments, R¹⁶ and R¹⁷ are each independently hydrogen orC₁-C₃ alkyl. In certain embodiments, R¹⁶ and R¹⁷ are each independentlyhydrogen or methyl.

In certain embodiments, R¹⁸ and R¹⁹ are independently hydrogen ormethyl.

In certain embodiments, A is CR³; X is CH; R¹ is independently hydrogen,—OCH₃, —CF₃, —OCF₃, —CH₃, Cl or F, wherein both R¹ cannot be hydrogen atthe same time; R² is hydrogen; R³ is hydrogen or —CN; R⁴ is —NH—,—NHC(O)—, —NHC(O)NH— or —NHC(O)O—; and R⁵ is C₃-C₆ cycloalkyl optionallysubstituted by R¹⁰.

In certain embodiments, A is CR³; X is CH; R¹ is independently hydrogen,—OCH₃, —CF₃, —OCF₃, —CH₃, Cl or F, wherein both R¹ cannot be hydrogen atthe same time; R² is hydrogen; R³ is hydrogen or —CN; R⁴ is —NH—,—NHC(O)—, —NHC(O)NH— or —NHC(O)O—; and R⁵ is pyrimidinyl, pyridinyl,pyridazinyl or pyrazinyl optionally substituted by R¹⁰.

In certain embodiments, A is CR³; X is CR¹⁵; R¹ is independentlyhydrogen, —CN, Cl or F, wherein both R¹ cannot be hydrogen at the sametime; R² is hydrogen; R³ is hydrogen or —CN; R⁴ is —NH—; R⁵ ispyrimidinyl or pyridinyl optionally substituted by R¹⁰; and R¹⁵ ishydrogen, —CN or halogen.

In certain embodiments, A is CR³; X is CR¹⁵; R¹ is independentlyhydrogen, —CN, Cl or F, wherein both R¹ cannot be hydrogen at the sametime; R² is hydrogen; R³ is hydrogen or —CN; R⁴ is —NHC(O)—; R⁵ is C₃-C₆cycloalkyl optionally substituted by R¹⁰; and R¹⁵ is hydrogen, —CN orhalogen.

In certain embodiments, A is N; X is CR¹⁵; R¹ is independently hydrogen,—CN, Cl or F, wherein both R¹ cannot be hydrogen at the same time; R² ishydrogen; R⁴ is —NHC(O)—; R⁵ is C₃-C₆ cycloalkyl optionally substitutedby R¹⁰; and R¹⁵ is hydrogen, —CN or halogen.

In certain embodiments, A is N; X is CR¹⁵; R¹ is independently hydrogen,—CN, Cl or F, wherein both R¹ cannot be hydrogen at the same time; R² ishydrogen; R⁴ is —NH—; R⁵ is pyrimidinyl or pyridinyl optionallysubstituted by R¹⁰; and R¹⁵ is hydrogen, —CN or halogen.

In certain embodiments, R¹ is independently hydrogen or halogen, whereinboth R¹ cannot be hydrogen at the same time and R⁴ is —NH—, —NR⁶C(O)—,—NR⁶C(O)O— or —NR⁶C(O)NR⁷—.

Another embodiment includes a compound of Formula I, stereoisomers orpharmaceutically acceptable salts thereof, selected from:

-   2-(2,6-Dichlorophenyl)-N-(6-methyl-2-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-Dichlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   N-(6-(aminomethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   4-[4-(2-Amino-6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitrile;-   3-(6-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-ylamino)pyrimidin-4-yl)cyclobutanol;-   N-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-yl)cyclopropanecarboxamide;-   3-Chloro-5-fluoro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   {(3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-phenyl}-methanol;-   3,5-Dichloro-4-{4-[6-(2-hydroxy-ethylamino)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridin-2-yl}-benzonitrile;-   3,5-Dichloro-4-{4-[5-(3-hydroxy-azetidin-1-yl)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridine-2-yl}-benzonitrile;-   2-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-isonicotinonitrile;-   (2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridin-4-yl)methanol;-   N-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)acetamide;-   1-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-cyclopropylurea;-   1-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethane-1,2-diol;-   2-(2-Chloro-6-fluorophenyl)-N-(2-methyl-6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carbonitrile;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(dimethylamino)acetamide;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-hydroxyacetamide;-   2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   (6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methanol;-   2-(4-(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol;-   2-(2,6-Dichlorophenyl)-N-(1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   2-(2,6-dichlorophenyl)-N-(2-methyl-6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-dichlorophenyl)-N-(6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(4-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)piperazin-1-yl)ethanol;-   1-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)azetidin-3-ol;-   2-((6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(methyl)amino)ethanol;-   2,2′-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylazanediyl)diethanol;-   2-(2,6-dichlorophenyl)-N-(pyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-dichlorophenyl)-N-(pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylamino)ethanol;-   N-4-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)pyrimidine-4,6-diamine;-   2-(2-chloro-6-fluorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(6-methyl-2-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(4-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol;-   2-(4-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)piperazin-1-yl)ethanol;-   2-((6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(methyl)amino)ethanol;-   2,2′-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylazanediyl)diethanol;-   (6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methanol;-   1-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethane-1,2-diol;-   2-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylamino)ethanol;-   N-(2-(2-chlorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   2-(2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   methyl 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   methyl    2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-hydroxyacetamide;-   2-(2,6-dichlorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-4-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)pyrimidine-4,6-diamine;-   1-cyclopropyl-3-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)urea;-   2-(2-chlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   1-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-methylurea;-   N-4-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-N-6-methylpyrimidine-4,6-diamine;-   N-4-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-N-6-methylpyrimidine-4,6-diamine;-   2-(2,6-dichlorophenyl)-N-(6-((dimethylamino)methyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(6-((dimethylamino)methyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(dimethylamino)acetamide;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carbonitrile;-   N-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)acetamide;-   2-amino-N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   2-amino-N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   2-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)propan-2-ol;-   2-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)propan-2-ol;-   3-amino-N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)propanamide;-   1-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-methylurea;-   3-amino-N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)propanamide;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N-methylpyrimidine-4-carboxamide;-   (6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(morpholino)methanone;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N-methylpyrimidine-4-carboxamide;-   (2-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridin-4-yl)methanol;-   2-(2,6-dichlorophenyl)-N-(4-methylpyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(4-(aminomethyl)pyrimidin-2-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   N-(4-(aminomethyl)pyrimidin-2-yl)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   6-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-nicotinonitrile;-   3,5-Dichloro-4-[4-(2,6-dimethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridine-2-yl]-benzonitrile;-   Cyclopropanecarboxylic acid    [2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-amide;-   3,5-Dichloro-4-[4-(pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   1-[2-(2,6,-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-yl]-3-methyl-urea;-   3,5-Dichloro-4-[4-(6-morpholin-4-yl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridine-2-yl]-benzonitrile;-   3,5-Dichloro-4-(4-{6-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-4-ylamino}-thiazolo[5,4-c]pyridine-2-yl)-benzonitrile;-   3,5-Dichloro-4-[4-(5-hydroxymethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridine-2-yl}-benzonitrile;-   3,5-Dichloro-4-[4-(4-hydroxymethyl-pyridin-2-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-dimethylaminomethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   6-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidine-4-carboxylic    acid amide;-   N-{6-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-acetamide;-   3,5-Dichloro-4-[4-(5-hydroxymethyl-pyridin-2-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-methoxy-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(5-methyl-pyrazin-2-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-methyl-pyridazin-3-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   [2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-carbamic    acid methyl ester;-   3,5-Dichloro-4-[4-(6-methylamino-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   4-[4-(6-Amino-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitrile;-   3,5-Dichloro-4-{4-[6-(2-hydroxy-2-methyl-propylamino)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridin-2-yl}-benzonitrile;-   3-Chloro-4-[4-(2,6-dimethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-5-fluoro-benzonitrile;-   1-[2-(2-Chloro-4-cyano-6-fluoro-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-3-methyl-urea;-   2-(2,6-dichlorophenyl)-N-(pyrimidin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine;-   2-(2,6-dichlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine;-   [2-(2,6-dichlorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine;-   2-(4-(6-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-ylamino)pyrimidin-4-yl)piperazin-1-yl)ethanol;-   3-Chloro-5-fluoro-4-[4-(6-hydroxymethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   (6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(morpholino)methanone;-   2-(2-chloro-6-fluorophenyl)-N-(pyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(4-methylpyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-dichlorophenyl)-N-(pyridazin-3-yl)thiazolo[5,4-c]pyridin-4-amine;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carboxamide;-   2-(2-chloro-6-fluorophenyl)-N-(pyridazin-3-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)isonicotinonitrile;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazine-3-carboxamide;-   (6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazin-3-yl)(morpholino)methanone;-   (6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazin-3-yl)(morpholino)methanone;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N,N-dimethylpyridazine-3-carboxamide;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N,N-dimethylpyridazine-3-carboxamide;-   2-(2,6-dichlorophenyl)-N-(pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)isonicotinamide;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazine-3-carboxamide;-   N-(6-(aminomethyl)pyrimidin-4-yl)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   5-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrazine-2-carboxamide;    isopropyl    2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate; and-   1-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-(2-hydroxyethyl)urea.

Another embodiment includes a compound of Formula I, stereoisomers orpharmaceutically acceptable salts thereof, selected from:

-   2-(2,6-Dichlorophenyl)-N-(6-methyl-2-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-Dichlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   N-(6-(aminomethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   4-[4-(2-Amino-6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitrile;-   3-(6-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-ylamino)pyrimidin-4-yl)cyclobutanol;-   N-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-yl)cyclopropanecarboxamide;-   3-Chloro-5-fluoro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   {3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-phenyl}-methanol;-   3,5-Dichloro-4-{4-[6-(2-hydroxy-ethylamino)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridin-2-yl}-benzonitrile;-   3,5-Dichloro-4-{4-[5-(3-hydroxy-azetidin-1-yl)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridine-2-yl}-benzonitrile;-   2-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-isonicotinonitrile;-   (2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridin-4-yl)methanol;-   N-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)acetamide;-   1-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-cyclopropylurea;-   1-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethane-1,2-diol;-   2-(2-Chloro-6-fluorophenyl)-N-(2-methyl-6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carbonitrile;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(dimethylamino)acetamide;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-hydroxyacetamide;-   2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   (6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methanol;-   2-(4-(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol;-   2-(2,6-Dichlorophenyl)-N-(1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   2-(2,6-dichlorophenyl)-N-(2-methyl-6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-dichlorophenyl)-N-(6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(4-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)piperazin-1-yl)ethanol;-   1-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)azetidin-3-ol;-   2-((6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(methyl)amino)ethanol;-   2,2′-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylazanediyl)diethanol;-   2-(2,6-dichlorophenyl)-N-(pyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-dichlorophenyl)-N-(pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylamino)ethanol;-   N-4-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)pyrimidine-4,6-diamine;-   2-(2-chloro-6-fluorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(6-methyl-2-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(4-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol;-   2-(4-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)piperazin-1-yl)ethanol;-   2-((6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(methyl)amino)ethanol;-   2,2′-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylazanediyl)diethanol;-   (6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methanol;-   1-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethane-1,2-diol;-   2-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-ylamino)ethanol;-   N-(2-(2-chlorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   2-(2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   methyl 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   methyl    2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-hydroxyacetamide;-   2-(2,6-dichlorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-4-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)pyrimidine-4,6-diamine;-   1-cyclopropyl-3-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)urea;-   2-(2-chlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   1-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-methylurea;-   N-4-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-N-6-methylpyrimidine-4,6-diamine;-   N-4-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-N-6-methylpyrimidine-4,6-diamine;-   2-(2,6-dichlorophenyl)-N-(6-((dimethylamino)methyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(6-((dimethylamino)methyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(dimethylamino)    acetamide;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carbonitrile;-   N-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)acetamide;-   2-amino-N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   2-amino-N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   2-(6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)propan-2-ol;-   2-(6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)propan-2-ol;-   3-amino-N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)propanamide;-   1-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-methylurea;-   3-amino-N-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)propanamide;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N-methylpyrimidine-4-carboxamide;-   (6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(morpholino)methanone;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N-methylpyrimidine-4-carboxamide;-   (2-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridin-4-yl)methanol;-   2-(2,6-dichlorophenyl)-N-(4-methylpyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(4-(aminomethyl)pyrimidin-2-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   N-(4-(aminomethyl)pyrimidin-2-yl)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   6-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-nicotinonitrile;-   3,5-Dichloro-4-[4-(2,6-dimethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridine-2-yl]-benzonitrile;-   Cyclopropanecarboxylic acid    [2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-amide;-   3,5-Dichloro-4-[4-(pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   1-[2-(2,6,-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-yl]-3-methyl-urea;-   3,5-Dichloro-4-[4-(6-morpholin-4-yl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridine-2-yl]-benzonitrile;-   3,5-Dichloro-4-(4-{6-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-4-ylamino}-thiazolo[5,4-c]pyridine-2-yl)-benzonitrile;-   3,5-Dichloro-4-[4-(5-hydroxymethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridine-2-yl}-benzonitrile;-   3,5-Dichloro-4-[4-(4-hydroxymethyl-pyridin-2-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-dimethylaminomethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   6-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidine-4-carboxylic    acid amide;-   N-{6-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-acetamide;-   3,5-Dichloro-4-[4-(5-hydroxymethyl-pyridin-2-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-methoxy-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(5-methyl-pyrazin-2-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-methyl-pyridazin-3-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   [2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-carbamic    acid methyl ester;-   3,5-Dichloro-4-[4-(6-methylamino-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   4-[4-(6-Amino-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitrile;-   3,5-Dichloro-4-{4-[6-(2-hydroxy-2-methyl-propylamino)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridin-2-yl}-benzonitrile;-   3-Chloro-4-[4-(2,6-dimethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-5-fluoro-benzonitrile;-   1-[2-(2-Chloro-4-cyano-6-fluoro-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-3-methyl-urea;-   2-(2,6-dichlorophenyl)-N-(pyrimidin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine;-   2-(2,6-dichlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine;-   [2-(2,6-dichlorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine;-   2-(4-(6-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-ylamino)pyrimidin-4-yl)piperazin-1-yl)ethanol;-   3-Chloro-5-fluoro-4-[4-(6-hydroxymethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   (6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)(morpholino)methanone;-   2-(2-chloro-6-fluorophenyl)-N-(pyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(4-methylpyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-dichlorophenyl)-N-(pyridazin-3-yl)thiazolo[5,4-c]pyridin-4-amine;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carboxamide;-   2-(2-chloro-6-fluorophenyl)-N-(pyridazin-3-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)isonicotinonitrile;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazine-3-carboxamide;-   (6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazin-3-yl)(morpholino)methanone;-   (6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazin-3-yl)(morpholino)methanone;-   6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N,N-dimethylpyridazine-3-carboxamide;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N,N-dimethylpyridazine-3-carboxamide;-   2-(2,6-dichlorophenyl)-N-(pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)isonicotinamide;-   6-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridazine-3-carboxamide;-   N-(6-(aminomethyl)pyrimidin-4-yl)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-N-(pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   5-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrazine-2-carboxamide;    isopropyl    2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   1-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-(2-hydroxyethyl)urea;-   4-[4-(6-Amino-2-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitrile;-   3,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzamide;-   4-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3-chloro-5-fluorobenzonitrile;-   N-[2-(4-Amino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diamine;-   [2-(4-Amino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   {4-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3,5-dichlorophenyl}-methanol;-   N-[2-(4-Aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diamine;-   [2-(4-Aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   [2-(2,6-Dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   [2-(4-Azetidin-3-yl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   [2-(2,6-Dichloro-4-cyclopropylphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   1-{3,5-Dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-acetamide;-   [2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   N-[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diamine;-   [2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   [2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamic    acid methyl ester;-   3,5-Dichloro-4-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   2-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile;-   3-Chloro-2-[4-(6-hydroxymethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   2-[4-(6-Amino-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile;-   3-Chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3-Chloro-2-[7-fluoro-4-(6-hydroxymethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3-Fluoro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   7-bromo-2-(2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-chloro-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridine-7-carbonitrile;-   2-(2-cyano-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridine-7-carbonitrile;-   (2-(2-chloro-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-7-yl)methanol;-   (1S,2S)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamide;-   (1R,2R)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluoro-cyclopropane-carboxamide;-   (1R,2S)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(hydroxymethyl)cyclopropane-carboxamide;-   (1S,2R)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(hydroxymethyl)cyclopropane-carboxamide;-   2-(4-amino-2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   Cyclopropylmethyl    2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   2-(2,6-Dichlorophenyl)-N-(5-methylpyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-Chloro-6-fluorophenyl)-N-(5-methylpyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   5-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrazine-2-carbonitrile;-   (5-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrazin-2-yl)methanol;-   2-(2,6-Dichlorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   Cyclopropylmethyl    2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   2-(2,6-Dichlorophenyl)-N-(6-(morpholinomethyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-Chloro-6-fluorophenyl)-N-(6-(morpholinomethyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine;-   (R)-1-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethanol;-   (S)-1-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethanol;-   (R)-1-(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethanol;-   (S)-1-(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethanol;-   (R)—N-(6-(1-Aminoethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   (S)—N-(6-(1-Aminoethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   5-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrazine-2-carbonitrile;-   N-(5-(Aminomethyl)pyrazin-2-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-Dichlorophenyl)-N-(5-((methylamino)methyl)pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   (5-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrazin-2-yl)methanol;-   N-(5-(Aminomethyl)pyrazin-2-yl)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-Chloro-6-fluorophenyl)-N-(5-((methylamino)methyl)pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-N-methylpyridazine-3-carboxamide;-   Ethyl 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   Ethyl    2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   Isopropyl    2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate;-   1-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-(2-hydroxyethyl)urea;-   N2-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)pyrazine-2,5-diamine;-   N2-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)pyrazine-2,5-diamine;-   2-Cyano-N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide;-   N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-cyanoacetamide;-   N-(6-Cyclopropylpyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-Dichlorophenyl)-N-(5-ethylpyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   4-[(5-{[2-(2-Chloro-6-fluorophenyl)-[1,3]thiazolo[5,4-c]pyridin-4-yl]amino}pyrazin-2-yl)methyl]-1λ6,4-thiomorpholine-1,1-dione;-   2-(2,6-Dichlorophenyl)-N-(5-methylpyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2,6-Dichlorophenyl)-N-(5-ethylpyridin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-Chloro-6-fluorophenyl)-N-(5-ethylpyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   2-(2-Chloro-6-fluorophenyl)-N-(5-(morpholinomethyl)pyrazin-2-yl)thiazolo[5,4-c]pyridin-4-amine;-   N-(6-(1-Aminoethyl)pyrimidin-4-yl)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-amine;-   3-Fluoro-2-(4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)benzonitrile;-   2-(4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)-3-fluorobenzonitrile;-   3-Fluoro-2-(4-(6-(hydroxymethyl)pyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)benzonitrile;-   3-Fluoro-2-(4-(6-(methylamino)pyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)benzonitrile;-   N-(2-(2-Cyano-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide;-   (1S,2R)—N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamide;-   (1R,2S)—N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamide;-   N-[2-(4-Aminomethyl-2,6-dichlorophenyl)-thiazolo[5,4-c]pyridin-4-yl]-2-methylpyrimidine-4,6-diamine;-   Cyclopropanecarboxylic acid    [2-(4-amino-2,6-dichlorophenyl)-thiazolo[5,4-c]pyridin-4-yl]-amide;-   {6-[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-methanol;-   N-[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-2-methylpyrimidine-4,6-diamine;-   N-[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diamine;-   {6-[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-methanol;-   1-[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-3-methyl-urea;-   N-[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-2-methylpyrimidine-4,6-diamine;-   Cyclopropanecarboxylic acid    [2-(2,6-dichloro-4-cyano-phenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-amide;-   3,5-Dichloro-4-[7-fluoro-4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   4-[4-(6-Aminopyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2-yl]-3,5-dichlorobenzonitrile;-   3-Chloro-2-[4-(6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrile;-   Cyclopropanecarboxylic acid    [2-(2-chloro-6-cyanophenyl)-thiazolo[5,4-c]pyridin-4-yl]-amide;-   2-[4-(6-Aminopyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile;-   2-[4-(6-Amino-2-methyl-pyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile;-   Cyclopropanecarboxylic acid    [2-(2-chloro-6-cyanophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-amide;-   2-[4-(6-Aminopyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2-yl]-3-fluorobenzonitrile;-   3-Fluoro-2-[7-fluoro-4-(6-hydroxymethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   4-(6-aminopyrimidin-4-ylamino)-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine-7-carbonitrile;-   4-(6-aminopyrimidin-4-ylamino)-2-(2-cyano-6-fluorophenyl)thiazolo[5,4-c]pyridine-7-carbonitrile;-   5-chloro-4-(4-(2,6-dimethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)isophthalonitrile;-   4-(4-(6-aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)-5-chloroisophthalonitrile;-   2-(4-(2,6-dimethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)benzene-1,3,5-tricarbonitrile;-   2-[4-(2-Amino-6-methylpyrimidin-4-ylamino)-7-fluoro-thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile;-   3-Chloro-2-[7-fluoro-4-(2-hydroxymethyl-6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   2-[4-(6-Amino-2-methylpyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2-yl]-3-fluorobenzonitrile;-   3-Chloro-2-[7-fluoro-4-(6-hydroxymethyl-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrile;-   {6-[2-(4-Amino-2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-methanol;-   4-[4-(6-Methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichlorobenzamidine;-   3-Chloro-5-fluoro-2-[4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrile;-   2-[4-(2-Amino-6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile;-   3-Chloro-2-[4-(6-hydroxymethyl-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   3-Chloro-2-[4-(2-hydroxymethyl-6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile;-   [2-(4-Amino-2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine;-   3-Chloro-5-fluoro-2-[4-(6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrile;    and-   2-[4-(6-Amino-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3-chloro-5-fluorobenzonitrile.

The compounds of Formula I may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula I, includingbut not limited to: diastereomers, enantiomers, and atropisomers as wellas mixtures thereof such as racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula I incorporatesa double bond or a fused ring, both the cis- and trans-forms, as well asmixtures, are embraced within the scope of the invention. Both thesingle positional isomers and mixture of positional isomers, e.g.,resulting from the N-oxidation of the pyrimidinyl and pyrrozolyl rings,or the E and Z forms of compounds of Formula I (for example oximemoieties), are also within the scope of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the invention, asdefined by the claims, embrace both solvated and unsolvated forms.

In an embodiment, compounds of Formula I may exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention, as defined by the claims. The term “tautomer” or“tautomeric form” refers to structural isomers of different energieswhich are interconvertible via a low energy barrier. For example, protontautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons.

The present invention also embraces isotopically-labeled compounds ofFormula I, which are identical to those recited herein, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. All isotopes of any particular atom or element as specifiedare contemplated within the scope of the invention. Exemplary isotopesthat can be incorporated into compounds of Formula I include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O,¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certainisotopically-labeled compounds of Formula I (e.g., those labeled with ³Hand ¹⁴C) are useful in compound and/or substrate tissue distributionassays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes areuseful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements). Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of FormulaI can generally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples herein below, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

Synthesis of TYK2 Inhibitor Compounds

Compounds of Formula I may be synthesized by synthetic routes describedherein. In certain embodiments, processes well-known in the chemicalarts can be used, in addition to, or in light of, the descriptioncontained herein. The starting materials are generally available fromcommercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or arereadily prepared using methods well known to those skilled in the art(e.g., prepared by methods generally described in Louis F. Fieser andMary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y.(1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)), or Comprehensive HeterocyclicChemistry, Editors Katrizky and Rees, Pergamon Press, 1984.

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds of Formula I. Libraries of compounds of Formula I may beprepared by a combinatorial ‘split and mix’ approach or by multipleparallel syntheses using either solution phase or solid phase chemistry,by procedures known to those skilled in the art. Thus according to afurther aspect of the invention there is provided a compound librarycomprising at least 2 compounds of Formula I, enantiomers, diasteriomersor pharmaceutically acceptable salts thereof.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups (NH-Pg) includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protectionis readily determined by one skilled in the art. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

Compounds of the invention may be prepared from commercially availablestarting materials using the general methods illustrated herein.

For illustrative purposes, reaction Schemes 1-4 depicted below provideroutes for synthesizing the compounds of Formula I, as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be available and used.Although specific starting materials and reagents are depicted in theSchemes and discussed below, other starting materials and reagents maybe available for substitution to provide a variety of derivatives and/orreaction conditions. In addition, many of the compounds prepared by themethods described below can be further modified in light of thisdisclosure using conventional chemistry well known to those skilled inthe art.

Scheme 1 shows methods of preparing compounds of formulas 9 and 10,wherein R¹, R², R⁵ and A are as defined in Formula I. An aryl nitrile 1can be treated with ammonium sulfide to give thioamide 2. Thioamide 2can be reacted with methyl 3-bromo-2-oxopropanoate, followed by heatingin toluene with a catalytic amount of p-toluene sulfonic acid, to yieldthiazole ethyl ester 3. Ethyl ester 3 can be subsequently converted tothiazole aldehyde 4 through a two-step process. Wittig reaction ofaldehyde 4 with triphenyl phosphonium ylide provides α,β-unsaturatedmethyl ester 5. Hydrolysis, followed by treatment with oxalyl chlorideprovides acid chloride 6, which reacts with sodium azide to give an acylazide intermediate. This acyl azide intermediate can undergo Curtisrearrangement upon heating in Dowtherm A at 230° C., and subsequent ringclosure to arrive at pyridone 7. When treated with POBr₃, pyridone 7 canbe converted to pyridine 2-bromide intermediate 8, which could becoupled to an amine or amide under palladium-catalyzed conditions, tofurnish final products such as 9 or 10.

Scheme 2 shows an alternative method of preparing compounds of formulas9 and 10, wherein R¹, R², R⁵ and A are as defined in Formula I. The2-chloro-3-fluoroisonicotinic acid 11, can be converted to 4-aminopyridine 12 via a 2-step process. Amide coupling of 12 with an aryl acidchloride gives rise to amide 13. Amide 13 can then be transformed tochloroimidate intermediate 14 upon refluxing with thionyl chloride.Chloroimidate 14 can be treated with thio-urea, followed by heating inisopropanol, to generate thiazole 15. Thiazole 15 can be coupled with anamine or amide following the same palladium-catalyzed conditions as inScheme 1, to give 9 or 10. Furthermore, as shown in Scheme 2, it wasalso found that the 2-Cl pyridine intermediate 15 could be converted tothe 2-Br analog 16, which also can react with an amine or amide underpalladium-catalyzed conditions to give final products such as 9 or 10.

Scheme 3 shows an alternative general method for the preparation ofcompounds of formula 13, wherein R¹, R² and A are as defined in FormulaI. The 2-chloro-3-fluoropyridine 17 can be treated with lithiumdiisopropylamide in THF at −70° C., followed by reaction with iodine togive 2-chloro-3-fluoro-4-iodopyridine 18. Iodide 18 can be coupled witha primary amide 19 through a palladium-catalyzed reaction to providecompounds of formula 13.

Scheme 4 shows general methods of preparing pyrimidine analogs 25 and26, wherein R¹, R², R⁵ and A are as defined in Formula I.4,6-Dichloro-5-fluoropyrimidine 20 can be converted to aminointermediate 21 by heating with ammonia in n-butanol. Coupling aminointermediate 21 with an aryl acid chloride, in the presence of sodiumhydride, can give rise to amide 22. Reaction of 22 with P₂S₅ can givethiol 23, which can be methylated and then oxidized with mCPBA to givesulfone 24. When treated with an amine or an amide in the presence ofsodium hydride in DMF, sulfone 24 can be transformed to final products25 and 26.

It will be appreciated that where appropriate functional groups exist,compounds of various formulae or any intermediates used in theirpreparation may be further derivatised by one or more standard syntheticmethods employing condensation, substitution, oxidation, reduction, orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

In each of the exemplary Schemes it may be advantageous to separatereaction products from one another and/or from starting materials.Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g. an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diastereomeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g. (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). Bymethod (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Chiral LiquidChromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989);Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Pharmaceutical Compositions and Administration

Another embodiment provides pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments. In oneexample, compounds of Formula I may be formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation depends onthe particular use and the concentration of compound, and can rangeanywhere from about 3 to about 8. In one example, a compound of FormulaI is formulated in an acetate buffer, at pH 5. In another embodiment,the compounds of Formula I are sterile. The compound may be stored, forexample, as a solid or amorphous composition, as a lyophilizedformulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularpatient being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The “effective amount” of the compoundto be administered will be governed by such considerations, and is theminimum amount necessary to inhibit TYK2 kinase activity. For example,such amount may be below the amount that is toxic to normal cells, orthe patient as a whole.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing a compound of Formula I, which matricesare in the form of shaped articles, e.g. films, or microcapsules.Examples of sustained-release matrices include polyesters, hydrogels(for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers such as the LUPRON DEPOT™ (injectable microspherescomposed of lactic acid-glycolic acid copolymer and leuprolide acetate),and poly-D-(−)-3-hydroxybutyric acid.

In one example, the pharmaceutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 5-100 mg of thecompound of the invention.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal, inhaled and epidural andintranasal, and, if desired for local treatment, intralesionaladministration. Parenteral infusions include intramuscular, intravenous,intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, aerosols, etc. Such compositions may containcomponents conventional in pharmaceutical preparations, e.g., diluents,carriers, pH modifiers, sweeteners, bulking agents, and further activeagents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

An example of a suitable oral dosage form is a tablet containing about25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compound of the inventioncompounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodiumcroscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about1-10 mg magnesium stearate. The powdered ingredients are first mixedtogether and then mixed with a solution of the PVP. The resultingcomposition can be dried, granulated, mixed with the magnesium stearateand compressed to tablet form using conventional equipment. An exampleof an aerosol formulation can be prepared by dissolving the compound,for example 5-400 mg, of the invention in a suitable buffer solution,e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodiumchloride, if desired. The solution may be filtered, e.g., using a 0.2micron filter, to remove impurities and contaminants.

In one embodiment, the pharmaceutical composition also includes anadditional chemotherapeutic agent selected from an anti-proliferativeagent, an anti-inflammatory agent, an immunomodulatory agent, aneurotropic factor, an agent for treating cardiovascular disease, anagent for treating liver disease, an anti-viral agent, an agent fortreating blood disorders, an agent for treating diabetes, or an agentfor treating immunodeficiency disorders.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodimentincludes a pharmaceutical composition comprising a compound of FormulaI, or a stereoisomer or pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or excipient.

Another embodiment includes a pharmaceutical composition comprising acompound of Formula I, or a stereoisomer or pharmaceutically acceptablesalt thereof, for use in the treatment of an immunological orinflammatory disease. Another embodiment includes a pharmaceuticalcomposition comprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof for use in the treatment ofpsoriasis or inflammatory bowel disease.

Indications and Methods of Treatment

The compounds of the invention inhibit TYK2 kinase activity.Accordingly, the compounds of the invention are useful for reducinginflammation in particular patient tissue and cells. Compounds of theinvention are useful for inhibiting TYK2 kinase activity in cells thatoverexpress TYK2 kinase. Alternatively, compounds of the invention areuseful for inhibiting TYK2 kinase activity in cells in which, forexample, the type I interferon, IL-6, IL-10, IL-12 and IL-23 signalingpathway is disruptive or abnormal, for example by binding to TYK2 kinaseand inhibiting its activity. Alternatively, the compounds of theinvention can be used for the treatment of immunological or inflammatorydisorders.

Another embodiment includes a method of treating or lessening theseverity of a disease or condition responsive to the inhibition of TYK2kinase activity in a patient. The method includes the step ofadministering to a patient a therapeutically effective amount of acompound of Formula I, stereoisomers, tautomers or salts thereof.

In one embodiment, a compound of Formula I is administered to a patientin a therapeutically effective amount to treat or lessen the severity ofa disease or condition responsive to the inhibition of TYK2 kinaseactivity, and said compound is at least 15 fold, alternatively 10 fold,alternatively 5 fold or more selective in inhibiting TYK2 kinaseactivity over inhibiting each of the other Janus kinase activities.

Another embodiment includes a compound of Formula I, stereoisomers,tautomers or salts thereof for use in therapy.

Another embodiment includes a compound of Formula I, stereoisomers,tautomers or salts thereof for use in treating an immunological orinflammatory disease.

Another embodiment includes a compound of Formula I, stereoisomers,tautomers or salts thereof for use in treating psoriasis or inflammatorybowel disease.

Another embodiment includes the use of a compound of Formula I,stereoisomers, tautomers or salts thereof for treating an immunologicalor inflammatory disease.

Another embodiment includes the use of a compound of Formula I,stereoisomers, tautomers or salts thereof for treating psoriasis orinflammatory bowel disease.

Another embodiment includes the use of a compound of Formula I,stereoisomers, tautomers or salts thereof in the preparation of amedicament for the treatment of an immunological or inflammatorydisease.

Another embodiment includes the use of a compound of Formula I,stereoisomers, tautomers or salts thereof in the preparation of amedicament for the treatment of psoriasis or inflammatory bowel disease.

In one embodiment, the disease or condition is cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,immunological disease, atherosclerosis, restenosis, psoriasis, allergicdisorders, inflammatory disease, neurological disorders, ahormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, destructive bone disorders,proliferative disorders, infectious diseases, conditions associated withcell death, thrombin-induced platelet aggregation, liver disease,pathologic immune conditions involving T cell activation, CNS disordersor a myeloproliferative disorder.

In one embodiment, the disease or condition is cancer.

In one embodiment, the disease or condition is an immunologicaldisorder.

In one embodiment, the disease is a myeloproliferative disorder.

In one embodiment, the myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).

In one embodiment, the disease is asthma.

In one embodiment, the cancer is breast, ovary, cervix, prostate,testis, penile, genitourinary tract, seminoma, esophagus, larynx,gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicularcarcinoma, melanoma, lung, small cell lung carcinoma, non-small celllung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of thelung, colon, pancreas, thyroid, papillary, bladder, liver, biliarypassage, kidney, bone, myeloid disorders, lymphoid disorders, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivarygland, pharynx, small intestine, colon, rectum, anal, renal, prostate,vulval, thyroid, large intestine, endometrial, uterine, brain, centralnervous system, cancer of the peritoneum, hepatocellular cancer, headcancer, neck cancer, Hodgkin's or leukemia (including T-cell leukemia).

In one embodiment, the cardiovascular disease is restenosis,cardiomegaly, atherosclerosis, myocardial infarction or congestive heartfailure.

In one embodiment, the neurodegenerative disease is Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, Huntington'sdisease, and cerebral ischemia, and neurodegenerative disease caused bytraumatic injury, glutamate neurotoxicity or hypoxia.

In one embodiment, the inflammatory disease is inflammatory boweldisease, Crohn's disease, ulcerative colitis, rheumatoid arthritis,psoriasis, contact dermatitis or delayed hypersensitivity reactions.

In one embodiment, the inflammatory disease is asthma, inflammatorybowel disease, Crohn's disease, ulcerative colitis, rheumatoidarthritis, psoriasis, allergic rhinitis, atopic dermatitis, contactdermatitis or delayed hypersensitivity reactions.

In one embodiment, the autoimmune disease is lupus or multiplesclerosis.

In one embodiment, the disease is asthma, inflammatory bowel disease,Crohn's disease, pouchitis, microscopic colitis, ulcerative colitis,rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis,contact dermatitis, delayed hypersensitivity reactions, lupus ormultiple sclerosis.

Evaluation of drug-induced immunosuppression by the compounds of theinvention may be performed using in vivo functional tests, such asrodent models of induced arthritis and therapeutic or prophylactictreatment to assess disease score, T cell-dependent antibody response(TDAR), and delayed-type hypersensitivity (DTH). Other in vivo systemsincluding murine models of host defense against infections or tumorresistance (Burleson G R, Dean J H, and Munson A E. Methods inImmunotoxicology, Vol. 1. Wiley-Liss, New York, 1995) may be consideredto elucidate the nature or mechanisms of observed immunosuppression. Thein vivo test systems can be complemented by well-established in vitro orex vivo functional assays for the assessment of immune competence. Theseassays may comprise B or T cell proliferation in response to mitogens orspecific antigens, measurement of signaling through one or more of theJanus kinase pathways in B or T cells or immortalized B or T cell lines,measurement of cell surface markers in response to B or T cellsignaling, natural killer (NK) cell activity, mast cell activity, mastcell degranulation, macrophage phagocytosis or kill activity, andneutrophil oxidative burst and/or chemotaxis. In each of these testsdetermination of cytokine production by particular effector cells (e.g.,lymphocytes, NK, monocytes/macrophages, neutrophils) may be included.The in vitro and ex vivo assays can be applied in both preclinical andclinical testing using lymphoid tissues and/or peripheral blood (House RV. “Theory and practice of cytokine assessment in immunotoxicology”(1999) Methods 19:17-27; Hubbard A K. “Effects of xenobiotics onmacrophage function: evaluation in vitro” (1999) Methods; 19:8-16;Lebrec H, et al (2001) Toxicology 158:25-29).

Collagen-induced arthritis (CIA) is an animal model of human rheumatoidarthritis (RA). Joint inflammation, which develops in animals with CIA,strongly resembles inflammation observed in patients with rheumatoidarthritis (RA). Blocking tumor necrosis factor (TNF) is an efficacioustreatment of CIA, just as it is a highly efficacious therapy intreatment of RA patients. CIA is mediated by both T-cells and antibodies(B-cells). Macrophages are believed to play an important role inmediating tissue damage during disease development. CIA is induced byimmunizing animals with collagen emulsified in Complete Freund'sAdjuvant (CFA). It is most commonly induced in the DBA/1 mouse strain,but the disease can also be induced in Lewis rats.

The T-cell Dependent Antibody Response (TDAR) is An assay for immunefunction testing when potential immunotoxic effects of compounds need tobe studied. The IgM-Plaque Forming Cell (PFC) assay, using Sheep RedBlood Cells (SRBC) as the antigen, is currently a widely accepted andvalidated standard test. TDAR is an assay for adult exposureimmunotoxicity detection in mice based on the US National ToxicologyProgram (NTP) database (M. I. Luster et al (1992) Fundam. Appl. Toxicol.18:200-210). The utility of this assay stems from the fact that it is aholistic measurement involving several important components of an immuneresponse. A TDAR is dependent on functions of the following cellularcompartments: (1) antigen-presenting cells, such as macrophages ordendritic cells; (2) T-helper cells, which are critical players in thegenesis of the response, as well as in isotype switching; and (3)B-cells, which are the ultimate effector cells and are responsible forantibody production. Chemically-induced changes in any one compartmentcan cause significant changes in the overall TDAR (M. P. Holsapple In:G. R. Burleson, J. H. Dean and A. E. Munson, Editors, Modern Methods inImmunotoxicology, Volume 1, Wiley-Liss Publishers, New York, N.Y.(1995), pp. 71-108). Usually, this assay is performed either as an ELISAfor measurement of soluble antibody (R. J. Smialowizc et al (2001)Toxicol. Sci. 61:164-175) or as a plaque (or antibody) forming cellassay (L. Guo et al (2002) Toxicol. Appl. Pharmacol. 181:219-227) todetect plasma cells secreting antigen specific antibodies. The antigenof choice is either whole cells (e.g. sheep erythrocytes) or solubleprotein antigens (T. Miller et al (1998) Toxicol. Sci. 42:129-135).

A compound of Formula I may be administered by any route appropriate tothe disease or condition to be treated. Suitable routes include oral,parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary, and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the route may vary with, for example, the conditionof the recipient. Where the compound of Formula I is administeredorally, it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound ofFormula I is administered parenterally, it may be formulated with apharmaceutically acceptable parenteral vehicle and in a unit dosageinjectable form, as detailed below.

A dose to treat human patients may range from about 5 mg to about 1000mg of a compound of Formula I. A typical dose may be about 5 mg to about300 mg of a compound of Formula I. A dose may be administered once a day(QD), twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein, such as an immunologic disorder (e.g. psoriasis orinflammation) or a hyperproliferative disorder (e.g., cancer). Incertain embodiments, a compound of Formula I is combined in apharmaceutical combination formulation, or dosing regimen as combinationtherapy, with a second therapeutic compound that has anti-inflammatoryor anti-hyperproliferative properties or that is useful for treating aninflammation, immune-response disorder, or hyperproliferative disorder(e.g., cancer). The second therapeutic agent may be a NSAID or otheranti-inflammatory agent. The second therapeutic agent may be achemotherapeutic agent. The second therapeutic agent of thepharmaceutical combination formulation or dosing regimen can havecomplementary activities to the compound of Formula I such that they donot adversely affect each other. Such compounds are suitably present incombination in amounts that are effective for the purpose intended. Inone embodiment, a composition of this invention comprises a compound ofFormula I, or a stereoisomer, geometric isomer, tautomer, solvate,metabolite, or pharmaceutically acceptable salt or prodrug thereof, incombination with a therapeutic agent such as an NSAID.

Another embodiment, therefore, includes a method of treating orlessening the severity of a disease or condition responsive to theinhibition of TYK2 kinase in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of Formula I,and further comprising, administering a second therapeutic agent.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein there is a time period while both (or all) activeagents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

In a particular embodiment of therapy, a compound of Formula I, or astereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, may be combinedwith other therapeutic, hormonal or antibody agents such as thosedescribed herein, as well as combined with surgical therapy andradiotherapy. Combination therapies according to the present inventionthus comprise the administration of at least one compound of Formula I,or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, and the use of atleast one other cancer treatment method, or immunological disordermethod. The amounts of the compound(s) of Formula I and the otherpharmaceutically active immunologic or chemotherapeutic agent(s) and therelative timings of administration will be selected in order to achievethe desired combined therapeutic effect.

In one embodiment, compounds of the present invention are coadministeredwith any of anti-IBD agents, including but not limited toanti-inflammatory drugs, such as sulfasalazine, mesalamine orcorticosteroids, such as budesonide, prednisone, cortisone orhydrocortisone, immune suppressing agents, such as azathioprine,mercaptopurine, infliximab, adalimumab, certolizumab pegol,methotrexate, cyclosporine or natalizumab, antibiotics, such asmetronidazole or ciprofloxacin, anti-diarrheals, such as psylliumpowder, loperamide or methylcellulose, laxatives, pain relievers, suchas NSAIDs or acetaminophen, iron supplements, vitamin B supplements,vitamin D supplements and any combination of the above. In anotherexample, compounds of the present invention are administered with (e.g.before, during or after) other anti-IBD therapies, such as surgery.

In one embodiment, compounds of the present invention are coadministeredwith any of anti-psoriasis agents, including but not limited to topicalcorticosteroids, vitamin D analogues, such as calcipotriene orcalcitriol, anthralin, topical retinoids, such as tazarotene,calcineurin inhibitors, such as tacrolimus or pimecrolimus, salicylicacid, coal tar, NSAIDs, moisturizing creams and ointments, oral orinjectible retinoids, such as acitretin, methotrexate, cyclosporine,hydroxyurea. immunomodulator drugs, such as alefacept, etanercept,infliximab or ustekinumab, thioguanine, and any combinations of theabove. In another example, compounds of the present invention areadministered with (e.g. before, during or after) other anti-psoriasistherapies, such as light therapy, sunlight therapy, UVB therarpy,narrow-band UVB therapy, Goeckerman therapy, photochemotherapy, such aspsoralen plus ultraviolet A (PUVA), excimer and pulsed dye lasertherapy, or in any combination of antipsoriasis agents andanti-psoriasis therapies.

In one embodiment, compounds of the present invention are coadministeredwith any of anti-asthmtic agents, including but not limited tobeta2-adrenergic agonists, inhaled and oral corticosteroids, leukotrienereceptor antagonist, and omalizumab. In another embodiment, compounds ofthe present invention are coadministered with an anti-asthmtic agentselected from a NSAID, combinations of fluticasone and salmeterol,combinations of budesonide and formoterol, omalizumab, lebrikizumab andcorticosteroid selected from fluticasone, budesonide, mometasone,flunisolide and beclomethasone.

Methods and Articles of Manufacture

Another embodiment includes a method of manufacturing a compound ofFormula I. The method includes: (a) reacting a compound of formula (i):

wherein Lv is a leaving group, for example a halogen, and X, A, R¹ andR² are as defined for Formula I, with a compound of the formula H—R⁴—R⁵under conditions sufficient to form a compound of Formula I; and

(b) optionally further functionalizing said above compound.

Certain embodiments include a compound of formula (I), stereoisomers orpharmaceutically acceptable salts thereof. Certain embodiments include acompound of formula (I), stereoisomers or pharmaceutically acceptablesalts thereof, wherein X, A, R¹ and R² are as defined for Formula I andthe group -Lv is a halogen, —OR or —OS(O)₁₋₂R, wherein R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl orheterocyclyl and R is independently optionally substituted. In certainembodiments, the group -Lv is halogen. Certain embodiments include acompound of formula (I) wherein the group -Lv is —Br or —I. Certainembodiments include a compound of formula (I) other than4-chloro-2-(2,3-difluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,3-dimethylphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-methoxyphenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-O—tolylthiazolo[5,4-c]pyridine,4-chloro-2-(2-(difluoromethoxy)phenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-fluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,3-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,4-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,4-dimethylphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-chlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,6-dimethylphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,5-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine,2-(2-bromophenyl)-4-chlorothiazolo[5,4-c]pyridine,4-chloro-2-(2,6-difluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,5-difluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,4-difluorophenyl)thiazolo[5,4-c]pyridine or4-chloro-2-(2,5-dimethyl)thiazolo[5,4-c]pyridine.

In certain embodiments, the conditions for reacting a compound offormula (I) with a compound of the formula H—R⁴—R⁵ include transitionmetal catalyzed reaction conditions. In one embodiment, the transitionmetal catalyst is selected from a platinum, palladium or coppercatalyst. In one embodiment, the catalyst is a Pd(0) catalyst. Pd(0)catalysts for use in the method include tetrakis(tri-optionallysubstituted phenyl)phosphine palladium(0) catalyst, wherein saidoptional substituents on phenyl are selected from -OMe, —CF₃, —OCF₃, -Meand -Et and dipalladium(0) catalysts, such astris(dibenzylideneacetone)dipalladium(0). In certain embodiments, theconditions include heating the reactants under basic conditions, forexample, in the presence of an inorganic base, for example, a cesium,potassium, ammonium, or sodium carbonate or bicarbonate base, forexample Cs₂CO₃. In certain embodiments, the conditions further includeligands to the transition metal catalyst. In one embodiment, a bidentateligand is included, for example, the bidentate ligand xantphos is added.

In certain embodiments, methods of manufacturing a compound of Formula Ioptionally include reacting a compound of formula (ii):

wherein X, R¹ and R² are as defined for Formula I, with a halogenatingreagent, for example a phosphorous oxyhalide, such as POBr₃ or POCl₃, toform a compound of formual (i), wherein Lv is a halogen. Thehalogenation reaction can optionally be performed in the presence of abase, such as an inorganic base, for example, a cesium, potassium,ammonium, or sodium carbonate, bicarbonate or hydroxide base.

Certain embodiments include a compound of formula (II), stereoisomers orpharmaceutically acceptable salts thereof.

Another embodiment includes a kit for treating a disease or disorderresponsive to the inhibition of aTYK2 kinase. The kit includes:

(a) a first pharmaceutical composition comprising a compound of FormulaI; and

(b) instructions for use.

In another embodiment, the kit further includes:

(c) a second pharmaceutical composition, which includes achemotherapeutic agent.

In one embodiment, the instructions include instructions for thesimultaneous, sequential or separate administration of said first andsecond pharmaceutical compositions to a patient in need thereof.

In one embodiment, the first and second compositions are contained inseparate containers.

In one embodiment, the first and second compositions are contained inthe same container.

Containers for use include, for example, bottles, vials, syringes,blister pack, etc. The containers may be formed from a variety ofmaterials such as glass or plastic. The container includes a compound ofFormula I or formulation thereof which is effective for treating thecondition and may have a sterile access port (for example the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). The container includes a compositioncomprising at least one compound of Formula I. The label or packageinsert indicates that the composition is used for treating the conditionof choice, such as cancer. In one embodiment, the label or packageinserts indicates that the composition comprising the compound ofFormula I can be used to treat a disorder. In addition, the label orpackage insert may indicate that the patient to be treated is one havinga disorder characterized by overactive or irregular kinase activity. Thelabel or package insert may also indicate that the composition can beused to treat other disorders.

The article of manufacture may comprise (a) a first container with acompound of Formula I contained therein; and (b) a second container witha second pharmaceutical formulation contained therein, wherein thesecond pharmaceutical formulation comprises a chemotherapeutic agent.The article of manufacture in this embodiment of the invention mayfurther comprise a package insert indicating that the first and secondcompounds can be used to treat patients at risk of stroke, thrombus orthrombosis disorder. Alternatively, or additionally, the article ofmanufacture may further comprise a second (or third) containercomprising a pharmaceutically-acceptable buffer, such as bacteriostaticwater for injection (BWFI), phosphate-buffered saline, Ringer's solutionand dextrose solution. It may further include other materials desirablefrom a commercial and user standpoint, including other buffers,diluents, filters, needles, and syringes.

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare othercompounds of Formula I, and alternative methods for preparing thecompounds of Formula I are within the scope of this invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, and/or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the invention.

BIOLOGICAL EXAMPLES

Compounds of Formula I may be assayed for the ability to modulate theactivity of protein kinases, tyrosine kinases, additionalserine/threonine kinases, and/or dual specificity kinases in vitro andin vivo. In vitro assays include biochemical and cell-based assays thatdetermine inhibition of the kinase activity. Alternate in vitro assaysquantify the ability of the compound of Formula I to bind to kinases andmay be measured either by radiolabelling the compound of Formula I priorto binding, isolating the compound of Formula I/kinase complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where a compound of Formula I is incubated with knownradiolabeled ligands. These and other useful in vitro assays are wellknown to those of skill in the art.

In an embodiment, the compounds of Formula I can be used to control,modulate or inhibit tyrosine kinase activity, for example TYK2 kinaseactivity, additional serine/threonine kinases, and/or dual specificitykinases. Thus, they are useful as pharmacological standards for use inthe development of new biological tests, assays and in the search fornew pharmacological agents.

Example A JAK1, JAK2 and TYK2 Inhibition Assay Protocol

The activity of the isolated JAK1, JAK2 or TYK2 kinase domain wasmeasured by monitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently labeledon the N-terminus with 5-carboxyfluorescein using the Caliper LabChiptechnology (Caliper Life Sciences, Hopkinton, Mass.). To determine theinhibition constants (Ki) of Examples 1-240, compounds were dilutedserially in DMSO and added to 50 μL kinase reactions containing 1.5 nMJAK1, 0.2 nM purified JAK2 or 1 nM purified TYK2 enzyme, 100 mM HepespH7.2, 0.015% Brij-35, 1.5 μM peptide substrate, 25 μM ATP, 10 mM MgCl₂,4 mM DTT at a final DMSO concentration of 2%. Reactions were incubatedat 22° C. in 384-well polypropylene microtiter plates for 30 minutes andthen stopped by addition of 25 μL of an EDTA containing solution (100 mMHepes pH 7.2, 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTAconcentration of 50 mM. After termination of the kinase reaction, theproportion of phosphorylated product was determined as a fraction oftotal peptide substrate using the Caliper LabChip 3000 according to themanufacturer's specifications. Ki values were then determined using theMorrison tight binding model. Morrison, J. F., Biochim. Biophys. Acta.185:269-296 (1969); William, J. W. and Morrison, J. F., Meth. Enzymol.,63:437-467 (1979).

Example B JAK3 Inhibition Assay Protocol

The activity of the isolated JAK3 kinase domain was measured bymonitoring phosphorylation of a peptide derived from JAK3(Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg) fluorescently labeled onthe N-terminus with 5-carboxyfluorescein using the Caliper LabChiptechnology (Caliper Life Sciences, Hopkinton, Mass.). To determine theinhibition constants (Ki) of Examples 1-240, compounds were dilutedserially in DMSO and added to 50 μL kinase reactions containing 5 nMpurified JAK3 enzyme, 100 mM Hepes pH7.2, 0.015% Brij-35, 1.5 μM peptidesubstrate, 5 μM ATP, 10 mM MgCl₂, 4 mM DTT at a final DMSO concentrationof 2%. Reactions were incubated at 22° C. in 384-well polypropylenemicrotiter plates for 30 minutes and then stopped by addition of 25 μLof an EDTA containing solution (100 mM Hepes pH 7.2, 0.015% Brij-35, 150mM EDTA), resulting in a final EDTA concentration of 50 mM. Aftertermination of the kinase reaction, the proportion of phosphorylatedproduct was determined as a fraction of total peptide substrate usingthe Caliper LabChip 3000 according to the manufacturer's specifications.Ki values were then determined using the Morrison tight binding model.Morrison, J. F., Biochim. Biophys. Acta. 185:269-296 (1969); William, J.W. and Morrison, J. F., Meth. Enzymol., 63:437-467 (1979).

Example C Cell-Based Pharmacology Assays

The activities of compounds 1-240 were determined in cell-based assaysthat are designed to measure Janus kinase dependent signaling. Compoundswere serially diluted in DMSO and incubated with NK92 cells (AmericanType Culture Collection (ATCC); Manassas, Va.) in 384-well microtiterplates in RPMI medium at a final cell density of 50,000 cells per welland a final DMSO concentration of 0.2%. Human recombinant IL-12 (R&Dsystems; Minneapolis, Minn.) was then added at a final concentration of30 ng/ml to the microtiter plates containing the NK92 cells and compoundand the plates were incubated for 45 min at 37° C. Alternatively,compounds were serially diluted in DMSO and incubated with TF-1 cells(American Type Culture Collection (ATCC); Manassas, Va.) in 384-wellmicrotiter plates in OptiMEM medium without phenol red, 1%Charcoal/Dextran stripped FBS, 0.1 mM NEAA, 1 mM sodium pyruvate(Invitrogen Corp.; Carlsbad, Calif.) at a final cell density of 100,000cells per well and a final DMSO concentration of 0.2%. Human recombinantEPO (Invitrogen Corp.; Carlsbad, Calif.) was then added at a finalconcentration of 10 Units/ml to the microtiter plates containing theTF-1 cells and compound and the plates were incubated for 30 min at 37°C. Compound-mediated effects on STAT4 or STATS phosphorylation were thenmeasured in the lysates of incubated cells using the Meso ScaleDiscovery (MSD) technology (Gaithersburg, Md.) according to themanufacturer's protocol and EC₅₀ values were determined.

The compounds of Examples 1-126 were tested in the above assays andfound to have K_(i) values for TYK2 inhibition (Example A) of less thanabout 500 nM. The compounds of Examples 1-240 were tested in the aboveassays and found to have K_(i) values for TYK2 inhibition (Example A) ofless than about 500 nM. Table 0 below shows example K_(i) values forTYK2 inhibition (Example A).

TABLE 0 Example no. TYK2 Ki (nM) 2 0.5 9 1.4 10 23 16 1.4 18 0.3 22 1.024 6.2 25 87 56 8.6 129 1.6 138 4.1 213 1.5 223 0.4 224 0.3 227 0.8 2360.5

PREPARATIVE EXAMPLES Abbreviations

-   NH₄HCO₃ Ammonium hydrogen carbonate-   n-BuLi n-Butyllithium-   t-BuOH tert-Butanol-   CDCl₃ Deuterochloroform-   CH₃CN Acetonitrile-   Cs₂CO₃ Cesium carbonate-   DCE Dichloroethane-   DCM Dichloromethane-   DIPEA Diisopropylethylamine-   DME Ethyleneglycol dimethyl ether-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EtOAc Ethyl acetate-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   HPLC High Pressure Liquid Chromatography-   IMS Industrial methylated spirits-   LCMS Liquid Chromatography Mass Spectrometry-   MeOH Methanol-   MeOH-d₄ Deuteromethanol-   MgSO₄ Anhydrous magnesium sulfate-   NaHCO₃ Sodium hydrogen carbonate-   NaOH Sodium hydroxide-   Na₂SO₄ Anhydrous sodium sulfate-   NH₂ cartridge Isolute® silica-based sorbent with a chemically bonded    aminopropyl functional group-   POBr₃ Phosphorus oxybromide-   RPHPLC Reverse phase high pressure liquid chromatography-   RT Retention time-   SCX-2 Isolute® silica-based sorbent with a chemically bonded    propylsulfonic acid functional group-   p-TsOH p-Toluenesulfonic acid-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   Pd(dppf)Cl₂ (1,1′-Bis(diphenylphosphino)ferrocene)palladium(II)    dichloride-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

General Experimental Conditions

Compounds of this invention may be prepared from commercially availablestarting materials using the general methods illustrated herein.Specifically, 2,6-dichlorobenzoic acid, 2,6-dichlorobenzoyl chloride,2-choro-6-fluorobenzoic acid, 2,6-dichlorobenzonitrile,2-chloro-6-fluorobenzonitrile, 2-chloro-3-fluoropyridine-4-carboxylicacid, 2-chloro-3-fluoropyridine, were purchased from Aldrich (St. Louis,Mo.). 4,6-dichloro-5-fluoropyrimidine and 6-methylpyrimidine-4-aminewere purchased from Ark Pharm Inc. (Libertyville, Ill.).4,6-diaminopyrimidine was purchased from Allichem (Baltimore, Md.).6-chloropyrimidin-4-ylamine was purchased from Toronto ResearchChemicals (North York, Ontario). 4-amino-2,6-dimethylpyrimidine andcyclopropanecarboxamide were purchased from Alfa Aesar (Ward Hill,Mass.). All commercial chemicals, including reagents and solvents, wereused as received.

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (RT) and associated mass ions wereperformed using one of the following methods, with UV detectormonitoring at 220 nm and 254 nm, and mass spectrometry scanning 110-800amu in ESI+ ionization mode.

LCMS Analytical Methods

Final compounds were analyzed using a couple of LC/MS conditions, withUV detector monitoring at 220 nm and 254 nm, and mass spectrometryscanning 110-800 amu in ESI+ ionization mode.

LC/MS Method A: column: XBridge C18, 4.6×50 mm, 3.5 um; mobile phase: Awater (0.01% ammonia), B CH₃CN; gradient: 5%-95% B in 8.0 min; flowrate: 1.2 mL/min; oven temperature 40° C.

LC/MS Method B: column: XBridge C18, 4.6×50 mm, 3.5 um; mobile phase: Awater (10 mM ammonium hydrogen carbonate), B CH₃CN; gradient: 5%-95% Bin 8.0 min; flow rate: 1.2 mL/min; oven temperature 40° C.

LC/MS Method C: Experiments performed on a Waters Micromass ZQ2000quadrupole mass spectrometer linked to a Waters Acquity UPLC system witha PDA UV detector. The spectrometer has an electrospray source operatingin positive and negative ion mode. This system uses an Acquity BEH C181.7 um 100×2.1 mm column, maintained at 40° C. or an Acquity BEH ShieldRP18 1.7 μm 100×2.1 mm column, maintained at 40° C. and a 0.4 ml/minuteflow rate. The initial solvent system was 95% water containing 0.1%formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid(solvent B) for the first 0.4 minute followed by a gradient up to 5%solvent A and 95% solvent B over the next 5.6 minutes. This wasmaintained for 0.8 minutes before returning to 95% solvent A and 5%solvent B over the next 1.2 minutes. Total run time was 8 minutes.

LC/MS Method D: Experiments performed on a Waters Platform LC quadrupolemass spectrometer linked to a Hewlett Packard HP1100 LC system with adiode array and a Sedex 85 evaporative light scattering detector. Thespectrometer has an electrospray source operating in positive andnegative ion mode. This system uses a Phenomenex Luna 3 micron C18(2)30×4.6 mm column and a 2 ml/minute flow rate. The initial solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5minute followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4.0 minutes. This was maintained for 1 minute before returningto 95% solvent A and 5% solvent B over the next 0.5 minute. Total runtime was 6 minutes.

Method E: Experiments performed on a Waters ZMD quadrupole massspectrometer linked to a Waters 1525 LC system with a Waters 996 diodearray detector and a Sedex 85 evaporative light scattering detector. Thespectrometer has an electrospray source operating in positive andnegative ion mode. This system uses a Luna 3 micron C18(2) 30×4.6 mmcolumn and a 2 ml/minute flow rate. The initial solvent system was 95%water containing 0.1% formic acid (solvent A) and 5% acetonitrilecontaining 0.1% formic acid (solvent B) for the first 0.5 minutefollowed by a gradient up to 5% solvent A and 95% solvent B over thenext 4.0 minutes. This was maintained for 1 minute before returning to95% solvent A and 5% solvent B over the next 0.5 minute. Total run timewas 6 minutes. ¹H NMR spectra were recorded at ambient temperature usinga Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5 mmprobe. Chemical shifts are expressed in ppm relative totetramethylsilane. The following abbreviations have been used: br=broadsignal, s=singlet, d=doublet, dd=double doublet, t=triplet, q=quartet,m=multiplet.

Microwave experiments were carried out using a Biotage Initiator 60™which uses a single-mode resonator and dynamic field tuning. Temperaturefrom 40-250° C. can be achieved, and pressures of up to 30 bar can bereached.

Example 1

2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridine Step 1.N-(Pyridin-4-yl)pivalamide

A solution of pivaloyl chloride (13.4 g, 111 mmol) in DCM (20 mL) wasslowly added to a cooled (0° C.) solution of pyridin-4-amine (10 g, 106mmol) and triethylamine (26.7 g, 265 mmol) in DCM (80 mL). Afteraddition, the icebath was removed and the resulting mixture was stirredat 20° C. for 6 hours. The mixture was poured into water (100 mL) andextracted with DCM (3×100 mL). The combined organic extract was washedwith saturated NaHCO₃ solution (100 mL) and brine (100 mL), dried overMgSO₄, and concentrated under reduced pressure. The residue wasre-crystallized from EtOAc/petroleum ether to give the desired productas white crystals (7.9 g, 40% yield). LCMS (ESI) m/z: 179.1 [M+H⁺].

Step 2. 4-Pivalamidopyridin-3-yl diisopropylcarbamodithioate

To a cooled (−78° C.) solution of N-(pyridin-4-yl)pivalamide (2.50 g,14.0 mmol) in anhydrous THF (100 mL) was added n-BuLi (2.5 M in hexanes,12 mL, 29.4 mmol). The mixture was allowed to warm rapidly to 0° C. andstirred at this temperature for 1.5 hours. The resulting mixture wascooled to −78° C. again and a solution of tetraisopropylthiuramdisulfide (4.93 g, 14.0 mmol) in anhydrous THF (20 mL) was slowly added.After addition, the mixture was allowed to warm to room temperature, andthen water (200 mL) and EtOAc (200 mL) were added sequentially. Theorganic layer was separated, washed with water (2×200 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The mixture waspurified by silica gel column chromatography, eluting withEtOAc/petroleum ether (1:8) to give the desired product as a yellowsolid (2.46 g, 50% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.60 (d, J=7.5 Hz,1H), 8.50-8.45 (m, 2H), 8.40 (d, J=6.5 Hz, 1H), 1.60-1.11 (m, 14H), 1.29(s, 9H). LCMS (ESI) m/z: 354.2 [M+H⁺].

Step 3. 4-Aminopyridin-3-yl diisopropylcarbamodithioate

A mixture of 4-pivalamidopyridin-3-yl diisopropylcarbamodithioate (5.0g, 14 mmol) and NaOH (1.1 g, 28 mmol) in MeOH (100 mL) was stirred at20° C. for 20 hours. The reaction was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography, eluting with EtOAc/petroleum ether (1:8) to give thedesired product as a white solid (3.8 g, 93% yield). ¹H NMR (500 MHz,CDCl₃): δ 8.24 (t, J=2.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.90 (s, 2H),1.64-1.30 (m, 14H). LCMS (ESI) m/z: 270.1 [M+H⁺].

Step 4. 4-(2,6-Dichlorobenzamido)pyridin-3-yldiisopropylcarbamodithioate

A solution of 2,6-dichlorobenzoyl chloride (62 mg, 0.30 mmol) in DCM (4mL) was slowly added to a cooled (0° C.) solution of 4-aminopyridin-3-yldiisopropylcarbamodithioate (100 mg, 0.37 mmol) in DCM (15 mL). Thesolution was stirred at 20° C. for 30 minutes. The mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography, eluting with EtOAc/petroleum ether(1:4) to give the desired product as a yellow solid (20 mg, 15% yield).LCMS (ESI) m/z: 442.1 [M+H⁺].

Step 5. 2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridine

A solution of 4-(2,6-dichlorobenzamido)pyridin-3-yldiisopropylcarbamodithioate (50 mg, 0.11 mmol) in 5 M HCl (10 mL) wasstirred at 100° C. for 4 hours. The pH of the mixture was adjusted to 7by the addition of 2N sodium hydroxide solution and the aqueous phaseextracted with EtOAc (3×100 mL). The combined organic extract was washedwith water (2×50 mL) and brine (100 ml), dried over Na₂SO₄ andevaporated. The crude product was re-crystallized fromEtOAc/DCM/petroleum ether (1:10:10) to give the product as a white solid(24 mg, 76% yield). ¹H NMR (500 MHz, MeOH-d₄): δ 9.30 (s, 1H), 8.60 (d,J=5.5 Hz, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.54-7.50 (m, 3H). LCMS (MethodA): RT=4.84 min, m/z: 281.0 [M+H⁺].

Example 2

N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamideStep 1. 2,6-Dichlorobenzothioamide

A mixture of 2,6-dichlorobenzonitrile (100 g, 581 mmol), triethylamine(64.5 g, 640 mmol) and (NH₄)₂S (20% aqueous solution, 217 mL, 640 mmol)in pyridine (500 mL) was stirred at 50° C. for 4 hours. The mixture wasconcentrated under reduced pressure. The residue was dissolved in water(400 mL) and extracted with EtOAc (3×300 mL). The combined organicextract was washed with brine (100 mL), dried over Na₂SO₄, andconcentrated under reducuced pressure. The residue was re-crystallizedwith EtOAc/petroleum ether to afford the desired intermediate as a paleyellow solid (105 g, 88% yield). LCMS (ESI) m/z: 206.0 [M+H⁺].

Step 2. Ethyl 2-(2,6-dichlorophenyl)thiazole-4-carboxylate

A mixture of 2,6-dichlorobenzothioamide (15 g, 73 mmol) and3-bromo-2-oxopropanoate (28.4 g, 146 mmol) in DMF (200 mL) was stirredat 20° C. for 14 hours. The resulting mixture was then poured into water(100 mL), and extracted with EtOAc (3×100 mL). The combined organicextract was washed with brine (100 mL), dried over Na₂SO₄ andconcentrated under reducted pressure. The residue was dissolved intoluene (800 mL), p-TsOH (2.0 g) was added and the resulting mixture washeated at 120° C. for 4 hours. The mixture was concentrated underreduced pressure and the residue was purified via silica gel columnchromatography, eluting with EtOAc/petroleum ether (1:9) to give thedesired product as a brown solid (18 g, 82% yield). ¹H NMR (500 MHz,DMSO-d₆): δ 8.83 (s, 1H), 7.71-7.64 (m, 3H), 4.34 (q, J=9.0 Hz, 7.5 Hz,2H), 1.33 (t, J=9 Hz, 3H). LCMS (ESI) m/z: 301.1 [M+H⁺].

Step 3. (2-(2,6-Dichlorophenyl)thiazol-4-yl)methanol

To a cooled (0° C.) solution of ethyl2-(2,6-dichlorophenyl)thiazole-4-carboxylate (7.0 g, 23 mmol) in MeOH(100 mL) was added lithium borohydride (0.98 g, 47 mmol) in fourportions. After addition, the mixture was stirred at 0° C. for 1 hour.The reaction mixture was quenched with water (100 mL) and extracted withEtOAc (3×100 mL). The combined organic extract was washed with brine(100 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified via silica gel column chromatography eluting withEtOAc/petroleum ether (1:5) to give the desired product as a white solid(6.2 g, 97% yield). ¹H NMR (DMSO-d₆, 500 MHz): δ 7.74 (s, 1H), 7.66-7.64(m, 2H), 7.60-7.56 (m, 1H), 5.52 (t, J=5.5 Hz, 1H), 4.70 (m, 2H). LCMS(ESI) m/z: 260.1 [M+H⁺].

Step 4. 2-(2,6-Dichlorophenyl)thiazole-4-carbaldehyde

To a stirred solution of (2-(2,6-dichlorophenyl)thiazol-4-yl)methanol(5.8 g, 22 mmol) in EtOAc (200 mL) at room temperature was added2-iodoxybenzoic acid (12.5 g, 44.6 mmol). The resulting mixture waswarmed to 70° C. and stirred for 18 hours. The solid was removed viafiltration, and the filtrate concentrated under reduced pressure toafford the desired product as a white solid (5.8 g, ˜100% yield), whichwas used in the next step without further purification.

Step 5. (E)-Methyl 3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylate

To a cooled (0° C.) solution of Ph₃PCHCOOMe (7.5 g, 22 mmol) in DCM (200mL) was added a solution of2-(2,6-dichlorophenyl)thiazole-4-carbaldehyde (5.8 g, 22 mmol) in DCM(20 mL) dropwise. After addition, the resulting mixture was slowlywarmed to room temperature and stirred for 4 hours. The mixture wasconcentrated under reduced pressure and the residue was suspended inpetroleum ether (250 mL). The solid was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified via silica gel column chromatography eluting withEtOAc/petroleum ether (1:8) to afford the desired product as a whitesolid (6.3 g, 90% yield). LCMS (ESI) m/z: 314.1 [M+H⁺].

Step 6. (E)-3-(2-(2,6-Dichlorophenyl)thiazol-4-yl)acrylic acid

To a stirred solution of (E)-methyl3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylate (6.3 g, 20 mmol) in MeOH(100 mL) and H₂O (20 mL) was added lithium hydroxide (1.5 g, 61 mmol).The resulting mixture was stirred for 24 hours and then partiallyconcentrated under reduced pressure. The pH of the residual aqueousmixture was adjusted to 5 by addition of 2N HCl and extracted with EtOAc(3×100 mL). The combined organic extract was washed with brine (100 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, eluting with a 0-20%gradient of MeOH in DCM to give the desired product as a white solid(5.4 g, 94% yield). LCMS (ESI) m/z: 300.0 [M+H⁺].

Step 7. (E)-3-(2-(2,6-Dichlorophenyl)thiazol-4-yl)acryloyl chloride

To a suspension of (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylicacid (5.7 g, 19 mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g,38 mmol) and 2 drops of DMF. The resulting mixture was stirred for 2hours at room temperature and then concentrated under reduced pressureto give the crude desired product (6.0 g, 99% yield), which was used inthe next step without purification.

Step 8. (E)-3-(2-(2,6-Dichlorophenyl)thiazol-4-yl)acryloyl azide

To a cooled (0° C.) solution of sodium azide (6.2 g, 95 mmol) in water(100 mL) and acetone (100 mL) was added a solution of(E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acryloyl chloride (6.0 g, 19mmol) in dioxane (100 mL) dropwise. After addition, the resultingmixture was stirred for 1 hour at 0° C. The reaction was quenched withwater (50 mL) and extracted with EtOAc (3×80 mL). The combined organicextract was washed with brine (100 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The resultant residue was purifiedvia silica gel column chromatography eluting with EtOAc/petroleum ether(1:8) to afford the desired product as a yellow solid (6.0 g, 98%yield). LCMS (ESI) m/z: 325.0 [M+H⁺].

Step 9. 2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Dowtherm A® (20 mL) at 230° C. was added asolution of the (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acryloyl azide(0.33 g, 1.0 mmol) in dioxane (1.0 mL) dropwise over 15 minutes. Afteraddition, the resulting mixture was stirred for 1 hour at 230° C., andthen cooled to room temperature. The mixture was purified on a shortsilica gel column, eluting with petroleum ether then EtOAc/petroleumether (1:1) to give the desired product as a yellow solid (0.10 g, 31%yield). LCMS (ESI) m/z: 297.0 [M+H⁺].

Step 10. 4-Bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine

To a stirred solution of2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.32 g, 1.1mmol) in CH₃CN (50 ml) was added POBr₃ (0.918 g, 3.21 mmol). The mixturewas heated at 100° C. for 2 hours. The mixture was cooled to roomtemperature, quenched with ice (200 mL) and extracted with EtOAc (3×20mL). The combined organic extract was washed with saturated NaHCO₃ (100mL) and brine (100 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography eluting with a 0-10% gradient of EtOAc/petroleumether to give the desired product as a white solid (0.22 g, 56% yield).¹H NMR (500 MHz DMSO-d₆): δ 8.59 (d, J=5.5 Hz, 1H), 8.26 (d, J=6.0 Hz,1H), 7.76-7.74 (m, 2H), 7.71-7.68 (m, 1H). LCMS (ESI) m/z: 359.1 [M+H⁺].

Step 11.N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropane-carboxamide

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), cyclopropanecarboxamide (0.019 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g,0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34mmol) in dioxane (3 mL). The mixture was degassed with N₂ for 10 minutesand then irradiated in a microwave reactor at 160° C. for 2 hours. Aftercooling to room temperature the solid was removed via filtration. Thefiltrate was concentrated under reduced pressure and the residue waspurified by reverse phase column chromatography eluting with a 0-60%gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desired product as a whitesolid (13 mg, 21% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 11.44 (s, 1H),8.46 (d, J=6.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.72-7.67 (m, 3H),2.09-2.06 (m, 1H), 0.9-0.87 (m, 4H). LCMS (Method A): RT=5.84 min, m/z:371.0 [M+H⁺].

Example 3

2-(2,6-Dichlorophenyl)-N-(2,6-dimethylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 2,6-dimethylpyrimidin-4-amine (0.027 g, 0.22 mmol), Pd₂(dba)₃(0.013 g, 0.017 mmol), XantPhos ((0.017 g, 0.034 mmol) and Cs₂CO₃ (0.111g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N₂ for10 minutes and then irradiated in a microwave reactor at 160° C. for 2hours. After cooling to room temperature the solid was removed viafiltration. The filtrate was concentrated under reduced pressure and theresidue was purified with reverse phase column chromatography elutingwith a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desiredproduct as a white solid (14 mg, 21% yield). ¹H NMR (500 MHz, CH₃OH-d₄):δ 8.44 (d, J=5.5 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.56-7.51 (m, 4H),7.31 (s, 1H), 2.44 (s, 3H), 2.35 (s, 3H). LCMS (Method A): RT=5.75 min,m/z: 402.0 [M+H⁺].

Example 4

2-(2,6-Dichlorophenyl)-N-(6-methyl-2-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 6-methyl-2-morpholinopyrimidin-4-amine (0.043 g, 0.22 mmol),Pd₂(dba)₃ (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) andCs₂CO₃ (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassedwith N₂ for 10 minutes and then irradiated in a microwave reactor at160° C. for 2 hours. After cooling to room temperature the solid wasremoved via filtration. The filtrate was concentrated under reducedpressure and the residue was purified with reverse phase columnchromatography eluting with a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ togive the desired product as a white solid (25 mg, 31% yield). ¹H NMR(500 MHz, DMSO-d₆): δ 10.31 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 7.41 (d,J=5.5 Hz, 1H), 7.44-7.28 (m, 2H), 7.68-7.67 (m, 1H), 6.40 (s, 1H),3.55-3.54 (m, 8H), 2.21 (s, 3H). LCMS (Method A): RT=6.53 min, m/z:473.1 [M+H⁺].

Example 5

N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)acetamide

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), acetamide (0.013 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g, 0.017 mmol),XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34 mmol) in dioxane(3.0 mL). The mixture was degassed with N₂ for 10 minutes and thenirradiated in a microwave reactor at 160° C. for 2 hours. After coolingto room temperature the solid was removed via filtration. The filtratewas concentrated under reduced pressure and the residue was purifiedwith reverse phase column chromatography, eluting with a 0-60% gradientof CH₃CN in 0.5% NH₄HCO₃ to give the desired product as a white solid(25 mg, 44% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 11.14 (s, 1H), 8.49 (d,J=5.5 Hz, 1H), 7.93 (d, J=5.5 Hz, 1H), 7.74-7.20 (m, 2H), 7.67-7.65 (m,1H), 2.18 (s, 3H). LCMS (Method B): RT=5.02 min, m/z: 338.0 [M+H⁺].

Example 6

2-(2,6-Dichlorophenyl)-N-(1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4-amine

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 1H-pyrazol-4-amine (0.018 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g,0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34mmol) in dioxane (3.0 mL). The mixture was degassed with N₂ for 10minutes and then irradiated in a microwave reactor at 160° C. for 2hours. After cooling to room temperature the solid was removed viafiltration. The filtrate was concentrated under reduced pressure and theresidue was purified with reverse phase column chromatography elutingwith a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desiredproduct as a white solid (12 mg, 20% yield). ¹H NMR (500 MHz, CH₃OH-d₄):δ 8.27 (d, J=5.5 Hz, 1H), 8.12 (br, 1H), 7.74 (br, 1H), 7.64-7.58 (m,3H), 7.41-7.40 (d, J=5.5 Hz, 1H). LCMS (Method A): RT=4.94 min, m/z:362.0 [M+H⁺].

Example 7

2-(4-(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 2-(4-(6-amino-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol(0.052 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g, 0.017 mmol), XantPhos (0.017g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34 mmol) in dioxane (3.0 mL). Themixture was degassed with N₂ for 10 minutes and then irradiated in amicrowave reactor at 160° C. for 2 hours. After cooling to roomtemperature the solid was removed via filtration. The filtrate wasconcentrated under reduced pressure and the residue was purified withreverse phase column chromatography, eluting with a 0-60% gradient ofCH₃CN in 0.5% NH₄HCO₃ to give the desired product as a white solid (15mg, 18% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 10.16 (s, 1H), 8.38 (d,J=5.5 Hz, 1H), 7.74-7.70 (m, 4H), 6.70 (s, 1H), 4.46 (t, J=5.5 Hz, 1H),3.54-3.52 (m, 6H), 2.51-2.47 (m, 4H), 2.44-2.41 (m, 2H), 2.32 (s, 3H).LCMS (Method A): RT=5.52 min, m/z: 516.1 [M+H⁺].

Example 8

(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methanolStep 1. 6-Chloropyrimidin-4-amine

A mixture of 4,6-dichloropyrimidine (20 g, 0.14 mol) and NH₄OH (200 mL)was heated at 30° C. for 15 hours with stirring. The resultingprecipitate was collected via filtration, and the filter cake was washedwith water (100 mL). The resultant solid was purified by silica gelcolumn chromatography, eluting with EtOAc to give the desired product asa white solid (14 g, 81% yield). LCMS (ESI) m/z: 130.1 [M+H⁺].

Step 2. 6-Vinylpyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (6.5 g, 0.050 mol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (9.24 g, 0.060 mol),tetrakis(triphenylphosphine)-palladium(0) (3.9 g, 0.0030 mol) and sodiumcarbonate (21 g, 0.20 mol) in dioxane (300 mL) and H₂O (30 mL) wasstirred at 90° C. under nitrogen for 15 hours. The mixture wasconcentrated under reduced pressure and the residue was partitionedbetween EtOAc (400 mL) and water (150 mL). The organic layer wasseparated, dried over Na₂SO₄, and concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatographyeluting with DCM/MeOH (20:1) to give the desired product as a whitesolid (4.8 g, 80% yield). LCMS (ESI) m/z: 122.1 [M+H⁺].

Step 3. tert-Butyl 6-vinylpyrimidin-4-ylcarbamate

6-Vinylpyrimidin-4-amine (3.6 g, 0.030 mol) was dissolved in anhydrousTHF (50 mL) and a solution of sodium hexamethyldisilazide in THF (2M, 24mL) was added dropwise over 5 minutes. The reaction was stirred for 10minutes at room temperature, and then a solution ofdi-tert-butoxydicarbonate (10 g, 0.045 mol) in THF (20 mL) was addeddropwise over 10 minutes). The reaction was stirred for 3 hours and thendiluted with water (200 mL) and extracted with EtOAc (2×100 mL). Thecombined organic phase was washed with brine (200 mL), dried over MgSO₄and concentrated under reduced pressure. The resultant residue waspurified by silica gel column chromatography, eluting with DCM/MeOH(50:1) to afford the desired product (5.9 g, 90% yield). LCMS (ESI) m/z:222.1 [M+H⁺].

Step 4. tert-Butyl 6-formylpyrimidin-4-ylcarbamate

To a stirred solution of tert-butyl 6-vinylpyrimidin-4-ylcarbamate (4.4g, 0.020 mol) in MeOH (200 mL) at −78° C. was bubbled O₃ for 1 hour. N₂was bubbled through the mixture for 10 minutes and then dimethylsulfide(1.24 g, 0.020 mol) was added dropwise. After addition, the solvent wasremoved under reduced pressure to give the crude desired product (4.6 g,over 100% yield) which was used in the next step without purification.LCMS (ESI) m/z: 224.1 [M+H⁺].

Step 5. tert-Butyl 6-(hydroxymethyl)pyrimidin-4-ylcarbamate

To a stirred solution of the crude tert-butyl6-formylpyrimidin-4-ylcarbamate (4.6 g, 0.020 mol) in MeOH (100 mL) wasadded sodium borohydride (0.74 g, 0.020 mol) in four portions at roomtemperature. After addition, the resulting mixture was stirred for 1hour and then water (50 mL) was added. The solvent was removed underreduced pressure and the resulting aqueous residue was extracted withEtOAc (3×100 mL). The combined organic extract was washed with water (30mL) and brine (30 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified via silica gel column chromatography,eluting with DCM/MeOH (30:1) to give the desired product (1.4 g, 30%yield). LCMS (ESI) m/z: 226.0 [M+H⁺].

Step 6. (6-Aminopyrimidin-4-yl)methanol hydrochloric salt

Concentrated hydrochloric acid (0.80 mL) was added to a solution oftert-butyl-6-(hydroxymethyl)pyrimidin-4-ylcarbamate (0.50 g, 2.2 mmol)in MeOH (10 mL). The reaction was stirred at 25° C. for 1 hour and thenconcentrated under reduced pressure to give the desired compound (0.50g) as a pale yellow solid, which was used in the next step withoutfurther purification. LCMS (ESI) m/z: 126.0 [M+H⁺].

Step 7.(6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methanol

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), (6-aminopyrimidin-4-yl)methanol hydrochloride salt (0.052 g, 0.22mmol), Pd₂(dba)₃ (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol)and Cs₂CO₃ (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture wasdegassed with N₂ for 10 minutes and then irradiated in a microwavereactor at 160° C. for 2 hours. After cooling to room temperature thesolid was removed via filtration. The filtrate was concentrated underreduced pressure and the residue was purified with reverse phase columnchromatography, eluting with a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃to give the desired product as a white solid (20 mg, 24% yield). ¹H NMR(500 MHz, DMSO-d₆): δ 10.71 (s, 1H), 8.63 (s, 1H), 8.45 (d, J=5.5 Hz,1H), 7.85-7.66 (m, 5H), 5.58 (m, 1H), 4.49 (d, J=5.5 Hz, 2H). LCMS(Method B): RT=4.84 min, m/z: 404.0 [M+H⁺].

Example 9

2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylcarbamate

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), methyl carbamate (0.017 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g, 0.017mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34 mmol) indioxane (3.0 mL). The mixture was degassed with N₂ for 10 minutes andthen irradiated in a microwave reactor at 160° C. for 2 hours. Aftercooling to room temperature the solid was removed via filtration. Thefiltrate was concentrated under reduced pressure and the residue waspurified by reverse phase column chromatography, eluting with a 0-60%gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desired product as a whitesolid (12 mg, 20% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (br, 1H),8.44 (d, J=6.5 Hz, 1H), 7.92 (d, J=6.5 Hz, 1H), 7.75-7.69 (m, 3H), 3.7(s, 3H). LCMS (Method A): RT=5.60 min, m/z: 354.0 [M+H⁺].

Example 10

N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-hydroxyacetamide

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 2-hydroxyacetamide (0.017 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g,0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34mmol) in dioxane (3.0 mL). The mixture was degassed with N₂ for 10minutes and then irradiated in a microwave reactor at 160° C. for 2hours. After cooling to room temperature the solid was removed viafiltration. The filtrate was concentrated under reduced pressure and theresidue was purified by reverse phase column chromatography, elutingwith a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desiredproduct as a white solid (16 mg, 27% yield). ¹H NMR (DMSO-d₆, 500 MHz):δ 8.48 (d, J=7.0 Hz, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.75-7.65 (m, 3H),5.75 (t, J=7.0 Hz, 1H), 4.16 (d, J=7.0 Hz, 2H). LCMS (Method B): RT=4.73min, m/z: 354.0 [M+H⁺].

Example 11

N-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(dimethylamino)acetamide

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 2-(dimethylamino)acetamide (0.023 g, 0.22 mmol), Pd₂(dba)₃ (0.013g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34mmol) in dioxane (3.0 mL). The mixture was degassed with N₂ for 10minutes and then irradiated in a microwave reactor at 160° C. for 2hours. After cooling to room temperature the solid was removed viafiltration. The filtrate was concentrated under reduced pressure and theresidue was purified by reverse phase column chromatography, elutingwith a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desiredproduct as a white solid (15 mg, 25% yield). ¹H NMR (500 MHz, DMSO-d₆):δ 10.62 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.96 (d, J=6.0 Hz, 1H),7.74-7.65 (m, 3H), 3.24 (s, 2H), 2.49 (s, 6H). LCMS (Method B): RT=6.01min, m/z: 381.1 [M+H⁺].

Example 12

6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carbonitrileStep 1. 6-Aminopyrimidine-4-carbonitrile

A mixture of 6-chloropyrimidin-4-amine (3.0 g, 23 mmol), zinc (II)cyanide (5.4 g, 46 mmol) and tetrakis(triphenylphosphine)palladium(0)(1.3 g, 1.2 mmol) in dry DMF (50 mL) was heated to 120° C. undernitrogen atmosphere for 15 hours. EtOAc (100 mL) was added and theinsoluble precipitate was removed by filtration. The filtrate wasdiluted with water (100 mL), and extracted with EtOAc (3×50 mL). Thecombined organic extract was washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by reversephase column chromatography, eluting with a 0-60% gradient of CH₃CN in0.5% NH₄HCO₃ to give the desired product as a pale yellow solid (0.6 g,21% yield). LCMS (ESI) m/z: 121.2 [M+H⁺].

Step 2.6-(2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidine-4-carbonitrile

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17mmol), 6-aminopyrimidine-4-carbonitrile (0.029 g, 0.22 mmol), Pd₂(dba)₃(0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N₂ for10 minutes and then irradiated in a microwave reactor at 160° C. for 2hours. After cooling to room temperature the solid was removed viafiltration. The filtrate was concentrated under reduced pressure and theresidue was purified with reverse phase column chromatography, elutingwith a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desiredproduct as a white solid (21 mg, 35% yield). ¹H NMR (500 MHz, DMSO-d₆):δ 11.43 (s, 1H), 8.91 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.31 (s, 1H),8.00 (d, J=5.0 Hz, 1H), 7.76-7.67 (m, 3H). LCMS (Method B): RT=6.30 min,m/z: 399.0 [M+H⁺].

Example 13

N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamideProcedure A Step 1. 2-Chloro-6-fluorobenzothioamide

A mixture of 2-chloro-6-fluorobenzonitrile (100 g, 643 mmol),triethylamine (71.5 g, 707 mmol) and (NH₄)₂S (20% aqueous solution, 240ml, 707 mmol) in pyridine (500 mL) was stirred at 50° C. for 4 hours.After cooling to room temperature, the mixture was concentrated underreduced pressure. The residue was dissolved in water (400 mL) andextracted with EtOAc (3×300 mL). The combined organic extract was washedwith brine (100 mL), dried over Na₂SO₄, and concentrated under reducedpressure. The resultant residue was re-crystallized from EtOAc andpetroleum ether to give the desired product as a pale yellow solid (101g, 78% yield). LCMS (ESI) m/z: 190.1 [M+H⁺].

Step 2. Ethyl 2-(2-chloro-6-fluorophenyl)thiazole-4-carboxylate

A mixture of 2-chloro-6-fluorobenzothioamide (15 g, 79 mmol) and3-bromo-2-oxopropanoate (30.8 g, 158 mmol) in DMF (200 mL) was stirredat 20° C. for 18 hours. The reaction mixture was poured into water (100mL) and extracted with EtOAc (3×100 mL). The combined organic extractwas washed with brine (100 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was dissolved in toluene (800 mL) andp-TsOH (2.0 g) was added. The mixture was heated at 120° C. for 4 hoursand then cooled to room temperature. The mixture was concentrated underreduced pressure and the residue was purified via silica gel columnchromatography, eluting with EtOAc/petroleum ether (1:10) to give thedesired product as a brown solid (17 g, 90% yield). ¹H NMR (500 MHz,DMSO-d₆): δ 7.70 (s, 1H), 7.35-7.07 (m, 3H), 4.52 (q, J=14.0 Hz, 7.5 Hz,2H), 1.35 (t, J=7.5 Hz, 3H). LCMS (ESI) m/z: 286.1 [M+H⁺].

Step 3. (2-(2-Chloro-6-fluorophenyl)thiazol-4-yl)methanol

To a cooled (0° C.) solution of ethyl2-(2-chloro-6-fluorophenyl)thiazole-4-carboxylate (7.0 g, 25 mmol) inMeOH (100 mL) was added lithium borohydride (1.62 g, 73.8 mmol) in fourportions. After addition, the resulting mixture was stirred at 0° C. for1 hour. The mixture was quenched with water (100 mL), and extracted withEtOAc (3×100 mL). The combined organic extract was washed with brine(100 mL), dried over Na₂SO₄, and concentrated under reduced pressure.The residue was purified via silica gel column chromatography, elutingwith EtOAc/petroleum ether (1:5) to give the desired product as a whitesolid (5.8 g, 98% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 7.74 (s, 1H),7.35-7.41 (m, 1H)NOT ENOUGH AR PROTONS, 5.47 (s, 1H), 4.67 (m, 2H). LCMS(ESI) m/z: 244.1 [M+H⁺].

Step 4. 2-(2-Chloro-6-fluorophenyl)thiazole-4-carbaldehyde

To a stirred solution of(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)methanol (5.8 g, 24 mmol) inEtOAc (200 mL) at room temperature was added 2-iodoxybenzoic acid (12.5g, 44.6 mmol). The resulting mixture was heated at 70° C. for 18 hours.After cooling to room temperature, the residual solid was removed viafiltration and the filtrate was concentrated under reduced pressure togive the crude desired product as a white solid (5.4 g, 93% yield) whichwas used in the next step without further purification.

Step 5. (E)-methyl 3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylate

To a cooled (0° C.) solution of Ph₃PCHCOOMe (7.5 g, 22 mmol) inanhydrous DCM (200 mL) was added a solution of2-(2-chloro-6-fluorophenyl)thiazole-4-carbaldehyde (5.4 g, 22 mmol) inDCM (20 mL) dropwise over 15 minutes. After addition, the resultingmixture was slowly warmed to room temperature and stirred for another 4hours. The mixture was concentrated under reduced pressure and theresidue was taken up in petroleum ether (250 mL). The resultingprecipitate was removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was purified via silica gel columnchromatography, eluting with EtOAc/petroleum ether (1:8) to give thedesired product as a white solid (6.0 g, 90% yield). LCMS (ESI) m/z:298.1 [M+H⁺].

Step 6. (E)-3-(2-(2-Chloro-6-fluorophenyl)thiazol-4-yl)acrylic acid

To a stirred solution of (E)-methyl3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylate (6.0 g, 20 mmol) inMeOH (100 mL) and H₂O (20 mL) was added lithium hydroxide (1.5 g, 61mmol). The resulting mixture was stirred at room temperature for 24hours and then partially concentrated under reduced pressure. The pH ofthe residue was adjusted to 5 by the addition of 2N HCl and the aqueousphase extracted with EtOAc (3×100 mL). The combined organic extract waswashed with brine (100 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluting with a 0-20% gradient of MeOH in DCM to give thedesired product as a white solid (5.4 g, 94% yield). LCMS (ESI) m/z:284.0 [M+H⁺]

Step 7. (E)-3-(2-(2-Chloro-6-fluorophenyl)thiazol-4-yl)acryloyl chloride

To a suspension of(E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylic acid (5.4 g, 19mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g, 38 mmol) and 2drops of DMF. The resulting mixture was stirred at room temperature for2 hours and then concentrated under reduced pressure to give the crudeproduct (5.7 g, 100% yield), which was used in the next step withoutpurification.

Step 8. (E)-3-(2-(2-Chloro-6-fluorophenyl)thiazol-4-yl)acryloyl azide

To a cooled (0° C.) solution of NaN₃ (6.2 g, 95 mmol) in water (100 mL)and acetone (100 mL) was added a solution of(E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acryloyl chloride (5.7 g,19 mmol) in dioxane (100 mL) dropwise over 15 minutes. After addition,the resulting mixture was stirred for another 1 hour at 0° C. Thereaction was quenched with water (50 mL) and extracted with EtOAc (3×100mL). The combined organic extract was washed brine (100 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified with silica gel column chromatography, eluting withEtOAc/petroleum ether (1:8) to give the desired product as a yellowsolid (5.3 g, 90% yield). LCMS (ESI) m/z: 309.0 [M+H⁺].

Step 9. 2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Dowthem A® (20 ml) at 230° C. was added asolution of (E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acryloylazide (0.30 g, 1.0 mmol) in dioxane (1.0 mL) dropwise over 15 minutes.After addition, the resulting mixture was stirred at 230° C. for 1 hourand then cooled to room temperature. The mixture was purified on a shortsilica gel column, eluting first with petroleum ether and then withEtOAc/petroleum ether (1:1) to give the desired product as a yellowsolid (0.10 g, 35% yield). LCMS (ESI) m/z: 281.0 [M+H⁺].

Step 10. 4-Bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine

To a stirred solution of2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.30 g, 1.1mmol) in MeCN (50 mL), was added POBr₃ (0.92 g, 3.2 mmol). The mixturewas heated at 100° C. for 2 hours and then cooled to room temperature.The reaction was quenched with ice and extracted with EtOAc (3×20 mL).The combined organic extract was washed with saturated NaHCO₃ solution(100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography eluting with a 0-10% gradient of EtOAc in petroleum etherto give the desired product as a white solid (0.22 g, 60% yield). ¹H NMR(500 MHz, DMSO-d₆): δ 8.59 (d, J=5.5 Hz, 1H), 8.27 (d, J=5.5 Hz, 1H),7.76-7.68 (m, 3H). LCMS (ESI) m/z: 342.9 [M+H⁺].

Step 11.N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide

To a microwave tube was added4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5mmol), cyclopropanecarboxamide (0.019 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g,0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34mmol) in dioxane (2.0 mL). The mixture was degassed with N₂ for 10minutes and then irradiated in a microwave reactor at 160° C. for 2hours. After cooling to room temperature, the solid was removed viafiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified with reverse phase column chromatography, elutingwith a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desiredproduct as a white solid (0.030 g, 59% yield). ¹H NMR (500 MHz,DMSO-d₆): δ 11.43 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.92 (d, J=6.0 Hz,1H), 7.72-7.68 (m, 1H), 7.67-7.59 (m, 1H), 7.52-7.49 (m, 1H), 2.09-2.06(m, 1H), 0.92-0.86 (m, 4H). LCMS (Method A): RT=6.30 min, m/z: 348.0[M+H⁺].

Procedure B Step 1.2-Chloro-N-(2-chloro-3-fluoro-pyridine-4-yl)-6-fluorobenzamide

A mixture of 2-chloro-3-fluoropyridin-4-ylamine (293 mg, 2.0 mmol),2-chloro-6-fluoro-benzoyl chloride (400 mg, 2.07 mmol) and triethylamine(300 μL, 218 mg, 2.15 mmol) in dioxane (6 mL) was heated at 50° C. for 4hours. After cooling to ambient temperature, triethylamine (60 μL) and2-chloro-6-fluorobenzoyl chloride (40 μL) were added. The resultantmixture was heated under reflux for a further 2 hours. The reactionmixture was cooled and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with DCM and theresultant solid was triturated in diethyl ether, filtered, and dried togive the desired compound as a white solid (380 mg, 63% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 11.46 (br s, 1H), 8.27-8.23 (m, 2H), 7.59 (td,J=8.3, 6.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.42-7.37 (m, 1H). LCMS(Method C): RT=3.34 min, m/z: 303 [M+H⁺].

Step 2. 2-Chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-6-fluorobenzimidoylchloride

A mixture of2-chloro-N-(2-chloro-3-fluoro-pyridine-4-yl)-6-fluorobenzamide (600 mg,2 mmol) and thionyl chloride (5 mL) was heated under reflux for 16 hoursthen cooled to ambient temperature. The reaction mixture was dilutedwith toluene (6 mL) and concentrated to dryness under reduced pressureto give the desired compound as a brown oil (650 mg, quant. yield). ¹HNMR (400 MHz, CDCl₃): δ 8.23 (d, J=5.1 Hz, 1H), 7.44 (td, J=8.3, 5.6 Hz,1H), 7.33 (d, J=8.2 Hz, 1H), 7.16 (t, J=8.7 Hz, 1H), 6.97 (t, J=5.1 Hz,1H).

Step 3. 4-Chloro-2-(2-chloro-6-fluoro-phenyl)-thiazolo[5,4-c]pyridine

A mixture of2-chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-6-fluorobenzimidoyl chloride(80 mg, 0.25 mmol), thiourea (76 mg, 1.0 mmol) and pyridine (82 μL, 1.0mmol) in anhydrous isopropanol (1.5 mL) was heated under reflux, undernitrogen, for 3.5 hours. The reaction mixture was allowed to cool toambient temperature and then triethylamine (1 mL) was added. Theresultant mixture was heated under reflux for a further 1 hour thencooled to ambient temperature. The mixture was concentrated to drynessunder reduced pressure and the residue was triturated with DCM, filteredand left to air dry. The crude product was purified by silica gel flashchromatography (0-10% EtOAc in cyclohexane) to give the desired compoundas a white solid (65 mg, 86% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.52 (d,J=5.6 Hz, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.50 (td, J=8.3, 5.8 Hz, 1H),7.41 (dt, J=8.2, 1.1 Hz, 1H), 7.21 (ddd, J=9.0, 8.4, 1.1 Hz, 1H). LCMS(Method C): RT=3.90 min, m/z: 299 [M+H⁺].

Step 4. Cyclopropanecarboxylic acid[2-(2-chloro-6-fluoro-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-amide

A mixture of4-chloro-2-(2-chloro-6-fluoro-phenyl)-thiazolo[5,4-c]pyridine (0.050 g,0.17 mmol), cyclopropanecarboxamide (0.016 g, 0.18 mmol), Pd₂(dba)₃(0.008 g, 0.009 mmol), XantPhos (0.010 g, 0.017 mmol) and cesiumcarbonate (0.139 g, 0.43 mmol) in dioxane (1.7 mL) was degassed withnitrogen then subjected to microwave irradiation at 170° C. for 60minutes. Further cyclopropanecarboxamide (0.006 g, 0.08 mmol), Pd₂(dba)₃(0.010 g, 0.010 mmol) and XantPhos (0.012 g, 0.021 mmol) were added. Themixture was degassed with nitrogen then subjected to microwaveirradiation at 200° C. for 90 minutes. Water and DCM were added and theresulting mixture was filtered through Celite®. The layers of thefiltrate were separated via a phase separator and the organic phaseconcentrated under reduced pressure. The residue was loaded onto anIsolute® SCX-2 cartridge that was washed with MeOH and the producteluted with 2M ammonia in MeOH. The relevant fractions were combined,concentrated under reduced pressure and the resultant residue waspurified by silica gel flash chromatography (0-30% EtOAc in DCM) to givethe desired compound as an off-white solid (0.018 g, 30% yield). ¹H NMR(300 MHz, DMSO-d₆): δ 11.40 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.92 (d,J=5.6 Hz, 1H), 7.69 (dd, J^(=8.3, 6.1) Hz, 1H), 7.59-7.58 (m, 1H),7.52-7.49 (m, 1H), 2.13-2.03 (s, 1H), 0.91-0.90 (m, 4H). LCMS (MethodD): RT=3.36 min, m/z: 348 [M+H⁺].

Example 14

2-(2-Chloro-6-fluorophenyl)-N-(2-methyl-6-morpholinopyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

To a microwave tube was added4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5mmol), 2-methyl-6-morpholinopyrimidin-4-amine (0.043 g, 0.22 mmol),Pd₂(dba)₃ (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) andCs₂CO₃ (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassedwith N₂ for 10 minutes and then irradiated in a microwave reactor at160° C. for 2 hours. After cooling to room temperature, the solid wasremoved via filtration and the filtrate was concentrated under reducedpressure. The residue was purified with reverse phase columnchromatography, eluting with a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃to give the desired product as a yellow solid (0.016 g, 24% yield). ¹HNMR (500 MHz, DMSO-d₆): δ 10.22 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.75(d, J=5.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.62-7.60 (m, 1H), 7.54-7.50 (m,1H), 6.75 (s, 1H), 3.69-3.67 (m, 4H), 3.52-3.50 (m, 4H), 2.33 (s, 3H).LCMS (Method A): RT=6.16 min, m/z: 457.1 [M+H⁺].

Example 15

1-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethane-1,2-diolStep 1. 1-(6-Aminopyrimidin-4-yl)ethane-1,2-diol

To a stirred suspension of 6-vinylpyrimidin-4-amine (700 mg, 5.78 mmol)in t-BuOH (25 mL) at room temperature was added a solution of OsO₄ (2%in t-BuOH, 3 mL). The resulting mixture was stirred at room temperaturefor 15 hours. The reaction was diluted with water (50 mL) and thenextracted with EtOAc (2×20 mL). The aqueous layer was lyophilized andthe residue was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS250 mm×20 mm×2, gradient: CH₃CN/10 mm/L NH₄HCO₃, 17 min) to give thedesired diol (160 mg, 18% yield) as a white solid. ¹H NMR (500 MHz,D₂O): δ 8.16 (s, 1H), 6.59 (s, 1H), 4.52 (m, 1H), 3.78 (m, 1H), 3.64 (m,1H). LCMS (ESI) m/z: 138.0 [M+H⁺].

Step 2.1-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)ethane-1,2-diol

To a microwave tube was added4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5mmol), 2-methyl-6-morpholinopyrimidin-4-amine (0.043 g, 0.22 mmol),Pd₂(dba)₃ (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) andCs₂CO₃ (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassedwith N₂ for 10 minutes and then irradiated in a microwave reactor at160° C. for 2 hours. After cooling to room temperature, the solid wasremoved via filtration and the filtrate was concentrated under reducedpressure. The residue was purified with reverse phase columnchromatography eluting with a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ togive the desired product as a yellow solid (0.040 g, 60% yield). ¹H NMR(500 MHz, DMSO-d₆): δ 10.72 (s, 1H), 8.64 (s, 1H), 8.46 (d, J=5.5 Hz,1H), 7.85 (d, J=5.5 Hz, 1H), 7.76-7.70 (m, 2H), 7.61-7.60 (m, 1H),7.54-7.52 (m, 1H), 5.57-5.56 (m, 1H), 4.76-4.74 (m, 1H), 4.50-4.47 (m,1H), 3.75-3.71 (m, 1H), 3.54-3.50 (m, 1H). LCMS (Method B): RT=4.33 min,m/z: 418.1 [M+H⁺].

Example 16

1-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-cyclopropylurea

Step 1. 1-cyclopropylurea. To a cooled (0° C.) mixture ofcyclopropylamine (8.0 g, 0.14 mol) in 5N HCl (28 mL) was added potassiumcyanate (11.3 g, 0.139 mol). The solution was stirred at 70° C. for 4hours, cooled to room temperature and then concentrated under reducedpressure. The residue was diluted with petroleum ether (100 mL). Theresulting precipitate was collected via filtration and washed withpetroleum ether (2×50 mL) to give the desired product as a white solid(2.0 g, 10% yield).

Step 2.1-(2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-cyclopropylurea

To a microwave tube was added4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5mmol), 1-cyclopropylurea (0.043 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g, 0.017mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34 mmol) indioxane (2.0 mL). The mixture was degassed with N₂ for 10 minutes andthen irradiated in a microwave reactor at 160° C. for 2 hours. Aftercooling to room temperature, solid was removed via filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified with reverse phase column chromatography eluting with a 0-60%gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desired product as ayellow solid (0.017 g, 26% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 9.64 (s,1H), 8.32 (d, J=7.5 Hz, 1H), 7.99 (br, 1H), 7.75-7.49 (m, 4H), 2.63 (m,1H), 0.72-0.66 (m, 2H), 0.52-0.46 (m, 2H). LCMS (Method A): RT=5.63 min,m/z: 363.0 [M+H⁺].

Example 17

N-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)acetamideStep 1. N-(6-aminopyrimidin-4-yl)acetamide

To a stirred suspension of pyrimidine-4,6-diamine (500 mg, 4.55 mmol) indioxane (20 mL) was added acetic anhydride (465 mg, 4.55 mmol) and theresulting mixture was heated under reflux for 15 hours. The reaction wascooled to room temperature and the resulting precipitate was collectedby filtration. The filtercake was dissolved in 1N HCl and the pH of theaqueous phase adjusted to 7 by the addition of 1N NaOH. The resultingwhite precipitate was collected by filtration and dried to afford thedesired product as a white solid (420 mg, 61% yield). LCMS (ESI) m/z:152.0 [M+H⁺].

Step 2.N-(6-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)acetamide

To a microwave tube was added4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5mmol), N-(6-aminopyrimidin-4-yl)acetamide (0.034 g, 0.22 mmol),Pd₂(dba)₃ (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) andCs₂CO₃ (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassedwith N₂ for 10 minutes and then irradiated in a microwave reactor at160° C. for 2 hours. After cooling to room temperature the solid wasremoved via filtration and the filtrate was concentrated under reducedpressure. The residue was purified with reverse phase columnchromatography eluting with a 0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ togive the desired product as a yellow solid (0.018 g, 27% yield). ¹H NMR(500 MHz, DMSO-d₆): δ 10.67 (s, 1H), 8.48-8.25 (m, 3H), 7.85-7.51 (m,4H), 2.12 (s, 3H). LCMS (Method A): RT=5.04 min, m/z: 415.0 [M+H⁺].

Example 18

(2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridin-4-yl)methanolStep 1. (2-Chloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester

To a mixture of 2-chloro-3-fluoroisonicotinic acid (3.55 g, 20.2 mmol)and triethylamine (8.4 mL, 6.13 g, 60.6 mmol) in dry toluene (40 mL) anddry t-BuOH (40 mL) under nitrogen, was added diphenylphosphoryl azide(6.51 mL, 8.27 g, 30.1 mmol). The reaction was heated at 110° C. for 3hours then cooled to ambient temperature. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in DCM(50 mL) and washed with water (40 mL). The aqueous phase was extractedwith DCM (2×40 mL) and the combined organic extract was dried overMgSO₄, and concentrated under reduced pressure. The residue was purifiedby silica gel flash chromatography (0-20% EtOAc in DCM) to give thetitle compound as a yellow oil (3.8 g, 71% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.09-8.07 (m, 2H), 6.98 (br s, 1H), 1.54 (s, 9H).

Step 2. 2-Chloro-3-fluoropyridin-4-ylamine

TFA (5 mL) was added to a solution of(2-chloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (1.9 g,7.7 mmol) in DCM (10 mL). The solution was stirred at ambienttemperature for 5 hours and concentrated under reduced pressure. Theresultant residue was dissolved in DCM and purified by columnchromatography on a NH₂ cartridge (0-10% MeOH in DCM) to afford thetitle compound as a beige solid (0.96 g, 94% yield). ¹H NMR (400 MHz,CDCl₃): δ 7.82 (d, J=5.4 Hz, 1H), 6.60 (t, J=5.8 Hz, 1H), 4.38 (br s,2H).

Step 3. 2,6-Dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzamide

A mixture of 2-chloro-3-fluoropyridin-4-ylamine (660 mg, 4.5 mmol),2,6-dichlorobenzoyl chloride (1.43 mL, 2.10 g, 10.0 mmol) andtriethylamine (1.53 mL, 1.11 g, 11.0 mmol) in dioxane (12 mL) was heatedunder reflux for 18 hours then cooled to ambient temperature. Theresultant mixture was partitioned between EtOAc (50 mL) and water (50mL). The organic layer was separated, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure. The residue wastriturated with diethyl ether, filtered, dried and further purified bysilica gel flash chromatography (0-25% EtOAc in pentane) to afford thetitle compound as a pink solid (1.17 g, 81% yield). ¹H NMR (300 MHz,CDCl₃): δ 8.50 (t, J=5.3 Hz, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.83 (br s,1H), 7.40-7.39 (m, 3H).

Step 4. 2,6-Dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzimidoylchloride

A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzamide(1.12 g, 3.5 mmol) and thionyl chloride (10 mL) was heated under refluxfor 18 hours then cooled to ambient temperature. The reaction mixturewas diluted with toluene (10 mL) and concentrated nder reduced pressureto afford the title compound as a pale brown solid (1.23 g, quant.yield). ¹H NMR (400 MHz, CDCl₃): δ 8.23 (d, J=5.1 Hz, 1H), 7.45-7.44 (m,2H), 7.38 (dd, J=9.4, 6.5 Hz, 1H), 6.98 (t, J=5.1 Hz, 1H).

Step 5. 4-Chloro-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine

A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzimidoylchloride (400 mg, 1.15 mmol), thiourea (305 mg, 4.0 mmol) and pyridine(325 μL, 4.0 mmol) in anhydrous isopropanol (6 mL) was heated underreflux under nitrogen for 3.5 hours. Triethylamine (1 mL) was added andheating was continued for a further 2 hours. The mixture was cooled toambient temperature and concentrated under reduced pressure. Theresultant residue was partitioned between DCM (15 mL) and water (15 mL).The aqueous phase was extracted with DCM (2×10 mL), the combined organicextract was dried over MgSO₄ and concentrated under reduced pressure.The residue was purified by silica gel flash chromatography (0-10% EtOAcin pentane) to give the title compound as a beige solid (270 mg, 74%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.52 (d, J=5.6 Hz, 1H), 7.98 (d,J=5.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.45 (dd, J=9.6, 6.2 Hz, 1H).

Step 6.(2-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyridin-4-yl)methanol

To a microwave tube was added4-chloro-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (70 mg, 0.22mmol), methyl carbamate (0.017 g, 0.22 mmol), Pd₂(dba)₃ (0.013 g, 0.017mmol), XantPhos (0.017 g, 0.034 mmol) and Cs₂CO₃ (0.11 g, 0.34 mmol) indioxane (3.0 mL). The mixture was degassed with N₂ for 10 minutes andthen irradiated in a microwave reactor at 140° C. for 2 hours. Aftercooling to room temperature, the solid was removed via filtration andthe filtrate was concentrated under reduced pressure. The residue waspurified with reverse phase column chromatography eluting with a 0-60%gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desired product as a whitesolid (45 mg, 50% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 10.17 (s, 1H),8.34 (d, J=5.5 Hz, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.73-7.59 (m, 5H), 6.90(d, J=5.0 Hz, 1H), 5.43 (t, J=5.0 Hz, 1H), 4.53 (d, J=5.5 Hz, 2H). LCMS(Method C): RT=5.36 min, m/z: 403.0 [M+H⁺].

Example 19

2-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-isonicotinonitrileStep 1.2,6-Dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzamide

2-Chloro-3-fluoropyridin-4-ylamine (146 mg, 1.0 mmol) was added to asuspension of sodium hydride (60% dispersed in mineral oil, 80 mg, 2.0mmol) in DMF (5 mL). The mixture was stirred for 30 minutes then2,6-dichloro-4-cyano-benzoyl chloride (250 mg, 1.1 mmol) was added andstirring continued for 18 hours. Water (10 mL) and DCM (20 mL) wereadded to the reaction, and the resultant mixture was acidified with 1MHCl. The organic phase was separated, washed with brine (10 mL), driedover MgSO₄, and concentrated to dryness under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting withDCM. The crude product was triturated with diethyl ether to give thedesired compound as a white solid (230 mg, 67% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.46 (t, J=5.3 Hz, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.88 (br s,1H), 7.72 (s, 2H).

Step 2.2,6-Dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzimidoylchloride

A mixture of2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzamide (1.2g, 3.4 mmol) and thionyl chloride (12.5 mL) was heated under reflux for18 hours then cooled to ambient temperature. The reaction mixture wasdiluted with toluene (10 mL) and concentrated to dryness under reducedpressure to afford the title compound as a white solid (1.23 g, 97%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.25 (d, J=5.1 Hz, 1H), 7.75 (s, 2H),6.97 (t, J=5.1 Hz, 1H).

Step 3.3,5-Dichloro-4-(4-chloro-thiazolo[5,4-c]pyridine-2-yl)-benzonitrile

A mixture of2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzimidoylchloride (454 mg, 1.25 mmol), thiourea (380 mg, 5.0 mmol) and pyridine(325 μL, 4.0 mmol) in anhydrous isopropanol (4 mL) was heated underreflux, under nitrogen, for 16 hours. Triethylamine (1.05 mL, 7.5 mmol)was added and the resultant mixture was heated under reflux for afurther 6.5 hours. The mixture was cooled to ambient temperature andconcentrated to dryness under reduced pressure. The residue waspartitioned between DCM (15 mL) and water (15 mL). The aqueous phase wasextracted with DCM (2×10 mL) and the combined organic extract was driedover MgSO₄ and concentrated to dryness under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with0-20% EtOAc in DCM. The resultant solid was triturated with cyclohexaneand dried under reduced pressure to give the desired compound as a whitesolid (275 mg, 65% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.55 (d, J=5.6 Hz,1H), 8.00 (d, J=5.6 Hz, 1H), 7.79 (s, 2H).

Step 4.4-(4-Bromo-thiazolo[5,4-c]pyridine-2-yl)-3,5-dichloro-benzonitrile

Trimethylsilylbromide (0.23 mL, 1.74 mmol) was added to a stirredsolution of3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridine-2-yl)-benzonitrile (295mg, 0.87 mmol) in propionitrile (11 mL) and the mixture heated at 90° C.for 48 hours. The reaction mixture was allowed to cool and poured onto amixture of saturated aqueous potassium carbonate solution and ice. DCMwas added and the organic phase was separated, dried over Na₂SO₄ andconcentrated to dryness under reduced pressure to give the desiredcompound as a white solid (322 mg, 96% yield). ¹H NMR (300 MHz, CDCl₃):δ 8.53 (d, J=5.5 Hz, 1H), 8.03-8.00 (m, 1H), 7.80 (s, 2H). LCMS (MethodD): RT=4.04 min, m/z: 386 [M+H⁺].

Step 5.2-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-isonicotinonitrile

Argon was bubbled through a suspension of4-(4-bromo-thiazolo[5,4-c]pyridine-2-yl)-3,5-dichloro-benzonitrile (92mg, 0.24 mmol), 2-amino-isonicotinonitrile (26 mg, 0.22 mmol), XantPhos(14 mg, 0.024 mmol) and cesium carbonate (195 mg, 0.6 mmol) in dioxane(2.5 ml) for 5 minutes then Pd₂(dba)₃ (11 mg, 0.012 mmol) was added. Thereaction was heated at 70° C. for 8 hours and then cooled to roomtemperature. The reaction was partitioned between water (10 mL) and DCM(20 mL). The organic layer was separated, dried over Na₂SO₄ andconcentrated to dryness under reduced pressure. The resultant residuewas purified by silica gel flash chromatography eluting with 0-60% EtOAcin DCM. The resultant solid was triturated with diethyl ether, filtered,and left to air dry to give the desired compound as a yellow solid (64mg, 63% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (br s, 1H), 8.50 (dd,J=5.1, 0.9 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.39 (s, 2H), 8.23 (s, 1H),7.79 (d, J=5.6 Hz, 1H), 7.38 (dd, J=5.1, 1.4 Hz, 1H). LCMS (Method C):RT=4.70 min, m/z: 423 [M+H⁺].

Example 20

3,5-Dichloro-4-{4-[5-(3-hydroxy-azetidin-1-yl)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridine-2-yl}-benzonitrileStep 1. 1-(6-Amino-pyrimidin-4-yl)-azetidin-3-ol

A solution of 3-azetidinol hydrochloride (454 mg, 4.1 mmol) in MeOH andwater was loaded onto an Isolute® SCX-2 cartridge that was washed withMeOH and the product eluted with 2M ammonia in MeOH. The relevantfractions were concentrated to dryness under reduced pressure. Theresultant residue was then added to a solution of6-chloro-pyrimidin-4-ylamine (151 mg, 1.16 mmol) in IMS (10 mL) underargon and heated under reflux for 18 hours. The reaction mixture wascooled and then loaded onto an Isolute® SCX-2 column. The column wasthen washed with MeOH and eluted with 2 M ammonia in MeOH. The relevantfractions were concentrated to dryness under reduced pressure and theresulting residue was purified by flash chromatography (NH₂ cartridge,0-5% MeOH in DCM) to give the desired compound as a white solid (163 mg,85% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.90 (d, J=1.0 Hz, 1H), 6.18(s, 2H), 5.65 (d, J=6.5 Hz, 1H), 5.21 (d, J=1.1 Hz, 1H), 4.54-4.53 (m,1H), 4.07 (dd, J=8.7, 6.7 Hz, 2H), 3.59 (dd, J=8.8, 4.6 Hz, 2H).

Step 2.3,5-Dichloro-4-{4-[5-(3-hydroxy-azetidin-1-yl)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridine-2-yl}-benzonitrile

Following the procedure described for2-[2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-isonicotinonitrile(Example 19),4-(4-bromo-thiazolo[5,4-c]pyridine-2-yl)-3,5-dichloro-benzonitrile and1-(6-amino-pyrimidin-4-yl)-azetidin-3-ol were reacted to give thedesired compound as a yellow solid (56 mg, 52% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 10.24 (s, 1H), 8.39 (d, J=5.5 Hz, 1H), 8.37 (s, 2H), 8.20(d, J=1.0 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 6.58 (s, 1H), 5.72-5.69 (m,1H), 4.63-4.56 (m, 1H), 4.20 (t, J=7.8 Hz, 2H), 3.73 (dd, J=9.1, 4.5 Hz,2H). LCMS (Method C): RT=3.21, m/z: 470 [M+H⁺].

Example 21

3,5-Dichloro-4-{4-[6-(2-hydroxy-ethylamino)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridin-2-yl}-benzonitrileStep 1.3,5-Dichloro-4-[4-(6-chloropyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

A mixture of4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.250g, 0.65 mmol), 4-amino-6-chloropyridine (0.080 g, 0.62 mmol), Pd₂(dba)₃(0.030 g, 0.033 mmol), XantPhos (0.038 g, 0.065 mmol) and cesiumcarbonate (0.530 g, 1.60 mmol) in dioxane (6.5 mL) was degassed withnitrogen then heated at 70° C. for 4 hours. The resulting mixture wasdiluted with DCM and water, and then filtered through Celite®. Thelayers of the filtrate were separated and the organic layer, dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel flash chromatography eluting with 0-25% EtOAc in pentaneand 0-10% EtOAc in DCM to give the desired compound as a yellow solid(0.215 g, 76% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 11.16 (s, 1H), 8.65(s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.39 (s, 2H), 7.97 (s, 1H), 7.91 (d,J=5.6 Hz, 1H). LCMS (Method E): RT=3.83 min, m/z: 433 [M+H⁺].

Step 2.3,5-Dichloro-4-{4-[6-(2-hydroxyethylamino)-pyrimidin-4-ylamino]-thiazolo[5,4-c]pyridin-2-yl}-benzonitrile

A mixture of3,5-dichloro-4-[4-(6-chloropyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile(0.030 g, 0.07 mmol) and ethanolamine (12.6 μL, 0.21 mmol) in NMP (0.7mL) was subjected to microwave irradiation at 150° C. for 75 minutes.Further ethanolamine (5.0 μL, 0.08 mmol) was added and the mixturesubjected to microwave irradiation at 160° C. for 45 minutes then 190°C. for 45 minutes. The reaction mixture was loaded onto an Isolute®SCX-2 cartridge that was washed with MeOH and the product eluted with 2Mammonia in MeOH. The relevant fractions were combined and concentratedunder reduced pressure. The residue was purified by silica gel flashchromatography (0-5% MeOH in DCM) to give the desired compound as anoff-white solid (0.014 g, 45% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.13(s, 1H), 8.40-8.34 (m, 3H), 8.16 (s, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.22(br s, 1H), 6.85 (br s, 1H), 4.72 (t, J=5.4 Hz, 1H), 3.52 (q, J=5.9 Hz,3H). LCMS (Method C): RT=3.10 min, m/z: 458 [M+H⁺].

Example 22

{3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-phenyl}-methanolStep 1. 2,6-Dichloro-4-iodobenzoyl chloride

A solution of 2,6-dichloro-4-iodobenzoic acid (5.50 g, 17.4 mmol) inthionyl chloride (52 mL) was heated under reflux for 2 hours thendiluted with toluene and concentrated under reduced pressure. Theresultant residue was partitioned between EtOAc and saturated aqueoussodium bicarbonate solution. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to give the desired compound as ayellow oil (5.75 g, 99% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 2H).

Step 2. 2,6-Dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-iodobenzamide

A mixture of 2-chloro-3-fluoropyridin-4-ylamine (1.73 g, 11.8 mmol),2,6-dichloro-4-iodobenzoyl chloride (5.90 g, 17.65 mmol) andtriethylamine (3.1 mL, 22.4 mmol) in dioxane (35 mL) was heated to 100°C. for 18 hours. The reaction mixture was partitioned between EtOAc andwater. The organic layer washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The resultant residue wastriturated with diethyl ether and dried under reduced pressure to givethe desired compound as a pink solid (2.83 g, 54% yield). ¹H NMR (300MHz, CDCl₃): δ 8.49-8.43 (m, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.82-7.73 (m,2H).

Step 3.2,6-Dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-iodobenzimidoylchloride

A solution of2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-iodobenzamide (2.83 g,6.4 mmol) in thionyl chloride (23 mL) was heated to 90° C. for 56 hoursthen diluted with toluene and concentrated under reduced pressure togive the desired compound (2.94 g, 99% yield). ¹H NMR (300 MHz, CDCl₃):δ 8.22 (d, J=5.1 Hz, 1H), 7.84-7.76 (m, 2H), 6.95 (t, J=5.1 Hz, 1H).

Step 4. 4-Chloro-2-(2,6-dichloro-4-iodo-phenyl)-thiazolo[5,4-c]pyridine

A mixture of2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-iodobenzimidoylchloride (2.94 g, 6.30 mmol), thiourea (1.93 g, 25.3 mmol) and pyridine(1.73 mL, 21.4 mmol) in isopropanol (25 mL) was heated to 90° C. for 3.5hours. Triethylamine (5.3 mL, 37.8 mmol) was added and the resultingmixture was heated to 90° C. for a further 1.5 h. The reaction wascooled to room temperature and then concentrated under reduced pressure.The resultant residue was partitioned between DCM and water. The organiclayer was separated, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was triturated with MeOH and dried under reducedpressure to give the desired compound (2.33 g, 84% yield). ¹H NMR (300MHz, CDCl₃): δ 8.52 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.90-7.81(s, 2H).

Step 5. 4-Chloro-2-(2,6-dichloro-4-vinyl-phenyl)-thiazolo[5,4-c]pyridine

A mixture of4-chloro-2-(2,6-dichloro-4-iodo-phenyl)-thiazolo[5,4-c]pyridine (0.30 g,0.68 mmol), vinyl borane pinacol ester (0.105 g, 0.68 mmol),PdCl₂(PPh₃)₂ (0.029 g, 0.04 mmol) and sodium carbonate (0.288 g, 2.70mmol) in water (0.4 mL) and dioxane (4 mL) was degassed with nitrogenand heated at 100° C. for 2 hours. The reaction mixture was cooled toroom temperature and then partitioned between EtOAc and water. Theorganic layer was separated, dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 0-8% EtOAc in pentane to give the desiredcompound as an off-white solid (0.168 g, 72% yield). ¹H NMR (300 MHz,CDCl₃): δ 8.51 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.53-7.45 (m,2H), 6.69-6.62 (m, 1H), 5.91 (d, J=17.5 Hz 1H), 5.52 (d, J=10.9 Hz, 1H).

Step 6.3,5-Dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-benzaldehyde

A solution of4-chloro-2-(2,6-dichloro-4-vinyl-phenyl)-thiazolo[5,4-c]pyridine (0.168g, 0.48 mmol) in DCM (3.8 mL) and MeOH (1 mL) was cooled to −78° C. anddegassed with nitrogen then compressed air before the ozone generatorwas turned on. After 10 minutes, a persistent grey colour remained sothe ozone generator was turned off and the reaction mixture was degassedwith nitrogen. Triphenylphosphine (0.125 g, 0.48 mmol) was added and themixture warmed to ambient temperature and stirred for 1 hour. Thereaction mixture was partitioned between DCM and water. The organiclayer dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with0-12% EtOAc in pentane to give the desired compound as an off-whitesolid (0.138 g, 84% yield). ¹H NMR (300 MHz, CDCl₃): δ 10.04 (s, 1H),8.55 (d, J=5.6 Hz, 1H), 7.99-7.98 (m, 3H).

Step 7.[3,5-Dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-phenyl]-methanol

A solution of3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-benzaldehyde(0.065 g, 0.19 mmol) in DCM (0.5 mL), MeOH (0.5 mL) and acetic acid (0.5mL) was treated with sodium cyanoborohydride (0.013 g, 0.21 mmol) andthe resultant mixture was stirred for 2 hours. The reaction mixture wasquenched with saturated aqueous sodium bicarbonate solution andpartitioned between DCM and water. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure to give the desiredcompound as an off-white solid (0.066 g, quant. yield). ¹H NMR (300 MHz,CDCl₃): δ 8.52 (d, J=5.6 Hz, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.49 (s, 2H),4.79 (s, 2H).

Step 8.{3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-phenyl}-methanol

A mixture of[3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-phenyl]-methanol(0.063 g, 0.18 mmol), 4-amino-6-methylpyrimidine (0.022 g, 0.20 mmol),Pd₂(dba)₃ (0.003 g, 3.6 pmol), XantPhos (0.003 g, 5.0 pmol) and cesiumcarbonate (0.117 g, 0.36 mmol) in dioxane (1.1 mL) was degassed withnitrogen and subjected to microwave irradiation at 150° C. for 30minutes. Further 4-amino-6-methylpyrimidine (0.011 g, 0.10 mmol),Pd₂(dba)₃ (0.006 g, 7.2 pmol), and XantPhos (0.006 g, 10.0 pmol) wereadded and the mixture subjected to further microwave irradiation at 150°C. for 60 minutes. The reaction mixture was diluted with MeOH and passedthrough a nylon filter. The filtrate was concentrated under reducedpressure then loaded onto an Isolute® SCX-2 cartridge which was washedwith MeOH and the product eluted with 2M ammonia in MeOH. The eluent wasconcentrated under reduced pressure and the resultant residue waspurified by silica gel flash chromatography eluting with 0-100% EtOAc inDCM to give the desired compound as a yellow solid (0.030 g, 40% yield).¹H NMR (300 MHz, CDCl₃): δ 8.68 (s, 1H), 8.42 (br s, 1H), 8.18-8.04 (m,1H), 7.77 (d, J=5.7 Hz, 1H), 7.50 (s, 2H), 4.72 (s, 2H), 2.55 (s, 3H).LCMS (Method C): RT=2.90 min, m/z: 418 [M+H⁺].

Example 23

3-Chloro-5-fluoro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo5,4-c]pyridin-2-yl-benzonitrile Procedure A Step 1.2-Chloro-N-(2-chloro-4-cyano-6-fluoro-benzoyl)-N-(2-chloro-3-fluoropyridin-4-yl)-4-cyano-6-fluorobenzamide

To a solution of 2-chloro-3-fluoropyridin-4-ylamine (1.05 g, 7.1 mmol)in DMF (25 mL) at 0° C. was added sodium hydride (0.343 g, 14.3 mmol).The resulting violet mixture stirred for 20 minutes before a solution of2-chloro-4-cyano-6-fluoro-benzoyl chloride (1.87 g, 8.6 mmol) in DMF (10mL) was added. The mixture was warmed to room temperature stirred for 16hours, then quenched with water and 1M HCl. The mixture was filteredthrough Celite®, washing with EtOAc. The organic filtrate was dried overNa₂SO₄ and concentrated under reduced pressure. The resultant residuewas purified by silica gel flash chromatography eluting with DCM to givethe desired compound as an off-white foam (0.869 g, 25% yield). ¹H NMR(300 MHz, CDCl₃): δ 8.24 (d, J=5.1 Hz, 1H), 7.55 (s, 2H), 7.36 (d, J=8.0Hz, 2H), 7.32-7.23 (m, 1H).

Step 2.2-Chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-6-fluorobenzamide

To a solution of2-chloro-N-(2-chloro-4-cyano-6-fluorobenzoyl)-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-6-fluoro-benzamide(0.865 g, 1.7 mmol) in MeOH (8.5 mL) and dioxane (8.5 mL) was addedsodium hydroxide (0.102 g, 2.5 mmol). The resulting mixture stirred atroom temperature for 2.5 hours and then concentrated under reducedpressure. The residue was partitioned between DCM and saturated aqueoussodium hydrogen carbonate solution. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel flash chromatography eluting with 0-100% DCM in pentane togive the desired compound as an off-white solid (0.308 g, 55% yield). ¹HNMR (300 MHz, CDCl₃): δ 8.49-8.40 (m, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.98(br s, 1H), 7.64 (t, J=1.3 Hz, 1H), 7.47 (dd, J=7.9, 1.5 Hz, 1H). LCMS(Method D): RT=3.33 min, m/z: 328 [M+H⁺].

Step 3.2-Chloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-cyano-6-fluorobenzimidoylchloride

A solution of2-chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-6-fluorobenzamide(0.805 g, 2.5 mmol) in thionyl chloride (7.5 mL) was heated under refluxfor 65 h then cooled to ambient temperature. The reaction mixture wasdiluted with toluene and concentrated under reduced pressure to give thedesired compound as a yellow solid (0.814 g, 96% yield). ¹H NMR (300MHz, CDCl₃): δ 8.25 (d, J=5.1 Hz, 1H), 7.70-7.63 (m, 1H), 7.49 (dd,J=8.0, 1.0 Hz, 1H), 6.97 (t, J=5.0 Hz, 1H). LCMS (Method D): RT=4.09min, m/z: 346 [M+H⁺].

Step 4.3-Chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile

A mixture of2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-cyano-6-fluorobenzimidoylchloride (0.713 g, 2.05 mmol), thiourea (0.623 g, 8.2 mmol) and pyridine(538 μL, 6.66 mmol) in isopropanol (7 mL) was heated under reflux for 3hours. The reaction mixture was allowed to cool to ambient temperaturebefore adding triethylamine (1.7 mL, 12.3 mmol). The resulting mixturewas heated under reflux for a further 3 hours and allowed to cool. Themixture was concentrated under reduced pressure and the residue wasparitioned between DCM and water. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The crude residue waspurified by silica gel flash chromatography (0-10% EtOAc in pentane) togive the desired compound as an off-white solid (0.356 g, 53% yield). ¹HNMR (300 MHz, CDCl₃): δ 8.55 (d, J=5.6 Hz, 1H), 8.01 (d, J=5.6 Hz, 1H),7.72 (t, J=1.4 Hz, 1H), 7.52 (dd, J=8.3, 1.5 Hz, 1H). LCMS (Method D):RT=3.86 min, m/z: 324 [M+H⁺].

Step 5.4-(4-Bromothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile

A suspension of3-chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile(0.077 g, 0.24 mmol) and trimethylsilyl bromide (63 μL, 0.48 mmol) inpropionitrile (2.4 mL) was heated under reflux for 5 hours beforefurther trimethylsilyl bromide (30 μL, 0.24 mmol) was added. Theresulting mixture was heated under reflux for a further 16 hours thenpartitioned between DCM and water. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure to give the desiredcompound as an off-white solid (0.090 g, quant. yield). ¹H NMR (300 MHz,CDCl₃): δ 8.53 (d, J=5.6 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H), 7.72 (t, J=1.4Hz, 1H), 7.52 (dd, J=8.3; 1.5 Hz, 1H). LCMS (Method D): RT=3.89 min,m/z: 368 [M+H⁺].

Step 6.3-Chloro-5-fluoro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

A mixture of4-(4-bromo-thiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluoro-benzonitrile(0.087 g, 0.24 mmol), 4-amino-6-methylpyrimidine (0.024 g, 0.22 mmol),Pd₂(dba)₃ (0.011 g, 0.01 mmol), XantPhos (0.014 g, 0.02 mmol) and cesiumcarbonate (0.192 g, 0.59 mmol) in dioxane (2.4 mL) was degassed withnitrogen and heated to 70° C. for 16 hours. The reaction mixture wasdiluted with DCM and water, and then filtered through Celite®. Thelayers of the filtrate were separated and the organic layer dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel flash chromatography eluting with 0-5% MeOH in DCM andtriturated with acetonitrile to give the desired compound as a yellowsolid (0.033 g, 35% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 10.70 (s, 1H),8.63 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.27 (t, J=1.3 Hz, 1H),8.22 (dd, J=9.0, 1.4 Hz, 1H), 7.85 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.39(s, 3H). LCMS (Method C): RT=3.30 min, m/z: 397 [M+H⁺].

Procedure B Step 1. 2-Chloro-3-fluoro-4-iodopyridine

A solution of lithium diisopropylamide (2M intetrahydrofuran/ethylbenzene/heptane, 155 mL, 0.31 mol) was addeddropwise over 40 minutes to solution of 2-chloro-3-fluoropyridine (31 g,0.235 mol) in tetrahydrofuran (200 mL) at −70° C. and the resultingmixture stirred for 4 hours. A solution of iodine (69 g, 0.2 mol) intetrahydrofuran (100 mL) was added dropwise over 30 minutes and theresultant mixture was stirred for 30 minutes at −70° C. then allowed towarm to room temperature over 1 hour. The reaction mixture was pouredonto aqueous sodium metabisulphite solution (20% w/v, 2 L) and extractedwith diethyl ether (3×300 mL). The combined organic extract was washedwith aqueous sodium metabisulphite solution (20% w/v, 2 L) and water(200 mL), dried over Na₂SO₄ and evaporated under reduced pressure togive a colorless oil. The resultant oil was triturated with diethylether to give the desired compound as a red/brown solid (28 g, 46%yield). ¹H NMR (400 MHz, CDCl₃): δ 7.87 (d, J=5.0 Hz, 1H), 7.66 (ddd,J=5.0, 4.0, 0.4 Hz, 1H).

Step 2. 2-chloro-4-cyano-6-fluoro-benzamide

A suspension of 2-chloro-4-cyano-6-fluoro-benzoic acid (8.5 g, 42.6mmol) and thionyl chloride (50 mL) was heated under reflux for 2 hours.The reaction mixture was allowed to cool to ambient temperature,evaporated to dryness and azeotroped with toluene (2×50 mL). Theresultant pale brown solid was dissolved in tetrahydrofuran (150 mL),cooled to 0° C. and a 2M solution of ammonia in isopropanol (600 mL) wasadded. After addition, the suspension was stirred for 1 hour thenconcentrated under reduced pressure to afford a white solid. The residuewas triturated with water (100 mL), the solid collected by filtrationand left to air dry to give the desired compound as a pale brown solid(7.5 g, 89% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (s, 1H), 8.06-7.99(m, 3H).

Step 3.2,6-Dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzamide

A mixture of 2-chloro-3-fluoro-4-iodopyridine (6.4 g, 24.8 mmol),2-chloro-4-cyano-6-fluoro-benzamide (6.0 g, 28.0 mmol), cesium carbonate(16.3 g, 49.6 mmol), XantPhos (1.45 g, 2.5 mmol) and Pd₂(dba)₃ (1.13 g,1.23 mmol) in dioxane (180 mL) was degassed with nitrogen then heatedunder reflux for 4 hours. The pale green suspension was allowed to coolto ambient temperature, poured into water (1200 mL) and extracted withEtOAc (2×500 mL). The combined organic layer was washed with water (500mL), dried over Na₂SO₄ and concentrated under reduced pressure to afforda yellow oil. The resultant oil was purified by silica gel flashchromatography eluting with 10-20% EtOAc in pentane to afford the titlecompound as a white solid (5.2 g, 64% yield). ¹H NMR (400 MHz, CDCl₃): δ8.45 (t, J=5.3 Hz, 1H), 8.24 (d, J=5.5 Hz, 1H), 8.03 (s, 1H), 7.63 (t,J=1.3 Hz, 1H), 7.46 (dd, J=8.0, 1.4 Hz, 1H). LCMS: RT=4.01 min, m/z: 328[M+H⁺].

Example 24

N-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-yl)cyclopropanecarboxamideStep 1. 6-chloro-5-fluoropyrimidin-4-amine

A mixture of 4,6-dichloro-5-fluoro-pyrimidine (1.67 g, 10.0 mmol),n-butanol (6 mL) and 28% ammonium hydroxide (12 mL) in a sealed tube washeated at 90° C. for 2 hours. The precipitated white crystals werecollected by filtration to give the desired compound (1.31 g, 89%yield). LCMS (ESI) m/z: 147.9 [M+H⁺].

Step 2. 2,6-dichloro-N-(6-chloro-5-fluoropyrimidin-4-yl)benzamide

To a solution of 6-chloro-5-fluoropyrimidin-4-amine (1.21 g, 8.2 mmol)in DMF (25 mL) at 0° C. was added NaH (60% in mineral oil, 0.46 g, 11.5mmol). The reaction mixture was stirred at 0° C. for 20 minutes.2,6-dichlorobenzoyl chloride (2.06 g, 9.8 mmol) was then added dropwiseover 5 minutes. The reaction mixture was warmed to room temperature andstirred under nitrogen overnight. The reaction was quenched withsaturated NH₄Cl solution (100 mL), and extracted with EtOAc (3×100 mL).The combined organics layer was dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography eluting with 0-25% EtOAc in hexane gradient to give thedesired compound as a white solid (1.32 g, 50% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.39 (s, 1H), 8.10 (s, 1H), 7.39-7.35 (m, 3H). LCMS (ESI) m/z:320.0 [M+H⁺].

Step 3. 2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidine-7-thiol

The mixture of 2,6-dichloro-N-(6-chloro-5-fluoropyrimidin-4-yl)benzamide(1.32 g, 4.1 mmol) and P₂S₅ (2.75 g, 12.4 mmol) in pyridine (8 mL) andxylene (32 mL) was heated at 120° C. for 7 hours. The mixture wasconcentrated under reduced pressure to give crude desired product, whichwas used in the next step without purification. LCMS (ESI) m/z: 313.9[M+H⁺].

Step 4. 2-(2,6-dichlorophenyl)-7-(methylthio)thiazolo[4,5-d]pyrimidine

To a solution of 2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidine-7-thiol(1.29 g, 4.1 mmol) and triethylamine (1.66 g, 16.4 mmol) in ethanol (20mL) was added methyl iodide (2.32 g, 16.4 mmol). The reaction mixturewas stirred at room temperature for 1 hour and then concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography eluting with 0-20% EtOAc/hexane gradient to give thedesired compound as a white solid (0.59 g, 44% yield). ¹H NMR (500 MHz,CDCl₃) δ 9.12 (s, 1H), 7.49-7.47 (M, 2H), 7.45-7.40 (m, 1H), 2.81 (s,3H). LCMS (ESI) m/z: 328.9 [M+H⁺].

Step 5.2-(2,6-dichlorophenyl)-7-(methylsulfonyl)thiazolo[4,5-d]pyrimidine

To a solution of2-(2,6-dichlorophenyl)-7-(methylthio)thiazolo[4,5-d]pyrimidine (627 mg,1.91 mmol) in DCM (10 mL) was added m-chloroperoxybenzoic acid (1.07 g,4.78 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was quenched with saturated aqueous sodiumhydrogen carbonate solution (30 mL). The organic layer was separated andthe aqueous layer was extracted with DCM (2×30 mL). The combined organicextract was dried over Na₂SO₄ and concentrated under reduced pressure.The crude product was purified by silica gel chromatography eluting with0-70% EtOAc/hexane gradient to give the desired compound as a whitesolid (271 mg, 40%). LCMS (ESI) m/z: 360.0 [M+H⁺].

Step 6.N-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-yl)cyclopropane-carboxamide

To a solution of cyclopropylcarboxamide (19 mg, 0.22 mmol) in DMF (1.5mL) at 0° C. was added NaH (9.8 mg, 0.24 mmol). The reaction mixture wasstirred at 0° C. for 10 minutes. A solution of2-(2,6-dichlorophenyl)-7-(methylsulfonyl)thiazolo[4,5-d]pyrimidine (940mg, 0.11 mmol) in DMF (0.5 mL) was then added at 0° C. The reactionmixture was warmed to room temperature and stirred for 2 hours. Thereaction was quenched with ice-water and extracted with EtOAc (3×25 mL).The combined organic extract was dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by reverse phaseHPLC (Gemini-NX, 3×10 cm, gradient: 30-70% CH₃CN/H₂O, 0.1% NH₄OH/H₂O,flow rate 60 mL/min, 10 min) to give the desired compound as a yellowsolid (12 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.98 (s,1H), 7.75-7.70 (m, 2H), 7.66 (dd, J=9.4, 6.6 Hz, 1H), 2.19-2.10 (m, 1H),0.95 (tt, J=7.6, 4.2 Hz, 4H). LCMS (Method B): RT=4.69 min, m/z: 365.0[M+H⁺].

Example 25

3-(6-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-ylamino)pyrimidin-4-yl)cyclobutanolStep 1.N-(6-chloropyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-amine

To a solution of 3-amino-6-chloropyrimidine (57 mg, 0.44 mmol) in DMF (2mL) at 0° C. was added NaH (24 mg, 0.61 mmol). The reaction mixture wasstirred at 0° C. for 10 minutes. A solution of2-(2,6-dichlorophenyl)-7-(methylsulfonyl)thiazolo[4,5-d]pyrimidine (88mg, 0.24 mmol) in DMF (1 mL) was then added at 0° C. The reactionmixture was warmed up to room temperature and stirred for 0.5 hour. Thereaction was quenched with ice-water and extracted with EtOAc (3×25 mL).The combined organic extract was dried over Na₂SO₄, and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography eluting with 5-50% EtOAc/hexanes gradient to give thedesired compound as a white solid (71 mg, 71%). ¹H NMR (400 MHz, DMSO) δ11.75 (s, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.76 (d, J=8.3Hz, 2H), 7.72-7.63 (m, 1H). LCMS (ESI) m/z: 490 [M+H⁺].

Step 2.3-(6-(2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidin-7-ylamino)pyrimidin-4-yl)cyclobutanol

The mixture ofN-(6-chloropyrimidin-4-yl)-2-(2,6-dichlorophenyl)-thiazolo[4,5-d]pyrimidin-7-amine(45 mg, 0.11 mmol), azetidin-3-ol hydrochloride (24 mg, 0.22 mmol) anddiisopropylamine (45 mg, 0.35 mml) in ethanol (1 mL) was heated at 130°C. under microwave radiation for 30 minutes. The reaction mixture wasconcentrated under reduced pressure. The crude product was purified byreverse phase HPLC (Gemini-NX, 3×10 cm, gradient: 5-85% CH₃CN/H₂O, 0.1%formic acid/H₂O, flow rate 60 mL/min, 10 min) to give the desiredcompound as a white solid (25 mg, 51% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 10.94 (s, 1H), 8.85 (s, 1H), 8.31 (d, J=0.8 Hz, 1H), 7.78-7.71 (m,2H), 7.67 (dd, J=9.4, 6.7 Hz, 1H), 6.54 (s, 1H), 5.79 (d, J=6.5 Hz, 1H),4.69-4.55 (m, 1H), 4.29-4.18 (m, 2H), 3.76 (dd, J=9.4, 4.4 Hz, 2H). LCMS(Method B): RT=3.55 min, m/z: 446.2 [M+H⁺].

Example 26

4-[4-(2-Amino-6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitriletrifluoroacetate salt Step 1.[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester

A mixture of4-(4-bromo-thiazolo[5,4-c]pyridin-2-yl)-3,5-dichloro-benzonitrile (0.578g, 1.50 mmol), tert-butyl carbamate (1.76 g, 15.0 mmol), Pd₂(dba)₃(0.069 g, 0.075 mmol), XantPhos (0.087 g, 0.15 mmol) and tribasicpotassium phosphate (0.635 g, 3.0 mmol) in toluene (10 mL) and water(1.5 mL) was degassed with argon then heated at 80° C. for 3 hours. Thereaction mixture was filtered through Celite® and washed with EtOAc. Thefiltrate was washed with water then brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The resultant residue was purifiedby silica gel flash chromatography (0-50% EtOAc in pentane) to give thedesired compound as an off-white solid (0.48 g, 76% yield). ¹H NMR (300MHz, CDCl₃): δ 8.35 (d, J=5.6 Hz, 1H), 7.79 (d, J=5.6 Hz, 1H), 7.75 (s,2H), 1.56 (s, 9H).

Step 2.4-(4-Amino-thiazolo[5,4-c]pyridin-2-yl)-3,5-dichloro-benzonitrile

A mixture of[2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester (0.48 g, 1.14 mmol) and TFA (2 mL) in DCM (8 mL)was stirred at room temperature for 2 hours then concentrated to drynessunder reduced pressure. The resultant residue was loaded onto anIsolute® SCX-2 cartridge which was washed with MeOH and the producteluted with 2M ammonia in isopropanol. The relevant fractions werecombined and concentrated under reduced pressure to afford the titlecompound as a pale yellow solid (0.309 g, 82% yield). ¹H NMR (300 MHz,CDCl₃): δ 8.21 (d, J=5.8 Hz, 1H), 7.77 (s, 2H), 7.50 (d, J=5.8 Hz, 1H),4.94 (s, 2H). LCMS (Method D): RT=2.04 min, m/z: 321 [M+H⁺].

Step 3.{4-[2-(2,6-Dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-6-methyl-pyrimidin-2-yl}-bis-carbamicacid tert-butyl ester

A mixture of4-(4-amino-thiazolo[5,4-c]pyridin-2-yl)-3,5-dichloro-benzonitrile (0.020g, 0.06 mmol), (4-chloro-6-methyl-pyrimidin-2-yl)-bis-carbamic acidtert-butyl ester (0.041 g, 0.12 mmol), Pd₂(dba)₃ (0.003 g, 0.003 mmol),XantPhos (0.0035 g, 0.006 mmol) and cesium carbonate (0.049 g, 0.15mmol) in dioxane (0.6 mL) was degassed with argon then heated at 80° C.for 1.5 hours. The reaction mixture allowed to cool to room temperature,the solid removed by filtration through Celite® and the filtrateconcentrated under reduced pressure. The resultant residue was purifiedby silica gel flash chromatography eluting with 0-60% EtOAc in pentaneto give the desired compound as a yellow glass (0.016 g, 42% yield). ¹HNMR (300 MHz, CDCl₃): δ 8.48 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 7.81-7.75(m, 2H), 7.65 (s, 1H), 2.57 (s, 3H), 1.46 (s, 18H). LCMS (Method D):RT=4.20 min, m/z: 628 [M+H⁺].

Step 4.4-[4-(2-Amino-6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitriletrifluoroacetate salt

A mixture of{4-[2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-6-methyl-pyrimidin-2-yl}-bis-carbamicacid tert-butyl ester (0.016 g, 0.025 mmol) and TFA (0.5 mL) in DCM (1mL) was stirred at room temperature for 2 hours then concentrated todryness under reduced pressure. The resultant residue was purified bysilica gel flash chromatography eluting with 0-5% MeOH in DCM to givethe desired compound as a yellow solid (0.0096 g, 71% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 11.35 (br s, 1H), 8.58-8.51 (m, 2H), 8.39 (s, 2H),8.05-7.98 (m, 2H), 7.68 (br s, 1H), 6.59 (s, 1H), 2.32 (s, 3H). LCMS(Method C): RT=3.16 min, m/z: 428 [M+H⁺].

Example 27

N-(6-(aminomethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amineStep 1. Methyl 6-aminopyrimidine-4-carboxylate

A mixture of 6-chloropyrimidin-4-amine (10.0 g, 77.2 mmol), PdCl₂(dppf)(6.0 g, 8.2 mmol), Et₃N (30 mL), MeOH (30 mL) in DMF (100 mL) was heated100° C. for 24 h under 20 atm CO (g) atmosphere. The solvents wereremoved under reduced pressure, and the residue was partitioned betweenwater (100 mL) and ethyl acetate (100 mL). The aqueous layer wasextracted with ethyl acetate (100 mL) three times. The combined organicphase was dried over Na₂SO₄ and concentrated. The resulting residue waspurified by silica gel column chromatography (0-10% MeOH/DCM) to givethe desired product as a gray solid (5.0 g, 42% yield). ¹H-NMR (500 MHz,DMSO-d₆): δ 8.44 (d, J=0.5 Hz, 1H), 7.27 (s, 2H), 7.03 (d, J=1.5 Hz,1H), 3.84 (s, 3H). LCMS (ESI) m/z: 154.1 [M+H⁺].

Step 2. (6-aminopyrimidin-4-yl)-methanol

To a stirred solution of methyl 6-aminopyrimidine-4-carboxylate (2.0 g,13 mmol) in MeOH (20 mL) at 25° C., was added LiBH₄ (0.85 g, 39 mmol).After addition, the resulting mixture was allowed to stir at 70° C. for16 hours. TLC indicated the starting material was consumed completely atthis point. Solvents were removed under reduced pressure and the residuewas purified via chromatography column on silica gel eluting with a 5%gradient of methanol in dichloromethane to give the desired alcohol aspale yellow oil (1.0 g, 61% yield). LCMS (ESI) m/z: 126.1 [M+H⁺].

Step 3. 2-((6-aminopyrimidin-4-yl)methyl)isoindoline-1,3-dione

To a stirred solution of (6-aminopyrimidin-4-yl)methanol (1.0 g, 8.0mmol), isoindoline-1,3-dione (1.4 g, 9.6 mmol), n-Bu₃P (2.42 g, 12.0mmol) in dry DMF (20 mL) at room temperature was added diisopropylazodicarboxylate (2.42 g, 12.0 mmol) dropwise. After addition, theresulting mixture was allowed to stir at 80° C. for 48 hours. Solventswere removed under reduced pressure and the residue was purified viachromatography column on silica gel eluting with a 2% gradient ofmethanol in dichloromethane to give the desired target as a gray solid(0.60 g, 30% yield). ¹H-NMR (500 MHz, DMSO-d₆): δ 8.22 (s, 1H),7.95-7.88 (m, 4H), 6.85 (s, 2H), 6.28 (s, 1H), 4.63 (s, 2H). LCMS (ESI)Method B: RT=3.23 min, m/z 233.1 [M+H⁺].

Step 4.2-((6-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino)pyrimidin-4-yl)methyl)isoindoline-1,3-dione

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (100 mg, 0.280mmol), 2-((6-aminopyrimidin-4-yl)methyl)isoindoline-1,3-dione (100 mg,0.390 mmol), Pd₂(dba)₃(32 mg, 0.035 mmol), XantPhos (30 mg, 0.052 mmol),Cs₂CO₃ (250 mg, 0.770 mmol) in dioxane (5.0 mL). The mixture wasdegassed with N₂ for 10 min. The resulting mixture was irradiated in amicrowave reactor at 160° C. for 2 hours and then cooled to roomtemperature. Insoluble solid was removed via filtration, and the residuewas purified with reverse phase column chromatography eluting with a0-60% gradient of CH₃CN in 0.5% NH₄HCO₃ to give the desired product as awhite solid (100 mg, 70% yield). LCMS: m/z: 533.1 [M+H⁺].

Step 5.N-(6-(aminomethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine

To a stirred solution ofN-(6-(aminomethyl)pyrimidin-4-yl)-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine(100 mg, 0.190 mmol) in EtOH (2.0 mL) in 25° C., was added 85% hydrazine(0.10 mL). The resulting mixture was stirred at the same temperature for30 min. TLC showed the starting material was consumed. Solvents wereremoved under reduced pressure and the residue was purified viaprep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient:CH₃CN/10 mm/L NH₄HCO₃, 17 min) to give the desired product as a paleyellow solid (14 mg, 19% yield). ¹H-NMR (500 MHz, DMSO-d₆): δ 8.64 (s,1H), 8.46 (d, J=5.5 Hz, 1H), 7.84 (d, J=5.5 Hz, 1H), 7.74-7.67 (m, 4H),3.73 (s, 2H). LCMS (ESI) Method B: RT=4.62 min, m/z: 403.1 [M+H⁺].

Additional compounds shown in Table 1 were also made according to theabove procedures.

TABLE 1 Synth. LCMS(ESI) LCMS R_(T) Example Structure Name Method m/z[M + H⁺] Method (min) NMR 28

2-(2,6- dichlorophenyl)-N- (2-methyl-6- morpholinopyrimidin- 4-yl)thiazolo[5,4- c]pyridin-4-amine 1 473.0 A 6.38 ¹H NMR (500 MHz, DMSO-d₆): δ 10.22 (s, 1H), 8.38 (d, J = 6.0 Hz, 1H), 7.75-7.69 (m, 3H),7.66-7.65 (m, 1H), 6.73 (s, 1H), 3.69-3.67(m, 4H), 3.51-3.35 (m, 4H),2.32 (s, 3H). 29

2-(2,6- dichlorophenyl)-N- (6- morpholinopyrimidin- 4- yl)thiazolo[5,4-c]pyridin-4-amine 1 459.0 A 5.93 ¹H NMR (500 MHz, DMSO- d₆): δ 10.28 (s,1H), 8.40 (d, J = 5.5 Hz, 1H), 8.28 (s, 1H), 7.76-7.25 (m, 3H),7.68-7.66 (m, 1H), 7.06 (s, 1H), 3.70-3.68 (m, 4H), 3.54-3.52 (m, 4H).30

2-(4-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4-yl)piperazin-1- yl)ethanol 1 402.1 A 5.10 ¹H NMR(500 MHz, DMSO- d₆): δ 10.31 (s, 1H), 8.40 (d, J = 6.0 Hz, 1H), 8.26 (s,1H), 7.75-7.65 (m, 4H), 7.02 (s, 1H), 4.46 (t, J = 6.0 Hz, 1H),3.56-3.52 (m, 6H), 2.50-2.48 (m, 4H), 2.45-2.42 (m, 2H). 31

1-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4-yl)azetidin-3-ol 1 445.0 A 4.92 ¹H NMR (500 MHz,DMSO- d₆): δ 10.22 (s, 1H), 8.91 (d, J = 6.0 Hz, 1H), 8.21 (s, 1H),7.75-7.38 (m, 3H), 7.22-7.68 (m, 1H), 6.64 (s, 1H), 5.77 (d, J = 6.0 Hz,1H), 4.62 (m, 1H), 4.22 (d, J = 6.0 Hz, 2H), 3.74 (d, J = 6.0 Hz, 2H).32

2-((6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4- yl)(methyl)amino) ethanol 1 447.1 A 5.20 ¹H NMR(500 MHz, CH₃OH- d₄): δ8.34 (d, J = 5.5 Hz, 1H), 8.24 (s, 1H), 7.72 (d,J = 5.5 Hz, 1H), 7.66-7.60 (m, 3H), 7.09 (s, 1H), 3.80-3.75 (m, 4H),3.20 (s, 1H). 33

2,2′-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4- ylazanediyl)diethanol 1 477.1 A 4.80 ¹H NMR (500MHz, DMSO- d₆): δ 10.05 (s, 1H), 8.32 (d, J = 6.0 Hz, 1H), 8.14 (s, 1H),7.66-7.64 (m, 3H), 7.60-7.57 (m, 1H), 6.82 (s, 1H), 4.77 (s, 2H), 3.52(s, 8H). 34

2-(2,6- dichlorophenyl)-N- (pyridin-2- yl)thiazolo[5,4-c]pyridin-4-amine 1 373.0 A 6.45 ¹H NMR (500 MHz, DMSO- d₆): δ 10.23 (s,1H), 8.36 (d, J = 5.5 Hz, 1H) 8.25 (d, J = 5.5 Hz, 1H), 7.74-7.66 (m,6H), 6.97 (m, 1H). 35

2-(2,6- dichlorophenyl)-N- (pyrimidin-4- yl)thiazolo[5,4-c]pyridin-4-amine 1 374.0 A 5.37 ¹H NMR (500 MHz, DMSO- d₆): δ 10.80 (s,1H), 8.76 (s, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.46 (d, J = 6.0 Hz, 1H),7.86-7.68 (m, 5H). 36

2-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4-ylamino)ethanol 1 433.0 A 4.76 ¹H NMR (500 MHz,CH₃OH- d₄): δ 8.42 (d, J = 5.5 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J = 5.5Hz, 1H), 7.70-7.60 (m, 3H), 7.21 (s, 1H), 3.75-3.73 (m, 2H), 3.49 (m,1H). 37

N-4-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-yl)pyrimidine-4,6-diamine 1 389.1 A 4.99 ¹H NMR (500 MHz, DMSO- d₆): δ 10.10 (s, 1H),8.36 (d, J = 5.5 Hz, 1H), 8.10 (s, 1H), 7.74-7.65 (m, 4H), 6.85 (s, 1H),6.64 (s, 1H). 38

2-(2-chloro-6- fluorophenyl)-N- (2,6- dimethylpyrimidin-4-yl)thiazolo[5,4- c]pyridin-4-amine 1 386.1 A 5.51 ¹H NMR (500 MHz,DMSO- d₆): δ 10.62 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 7.83 (d, J = 5.5Hz, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 1H), 7.55-7.51 (m, 1H), 7.30(s, 1H), 2.44 (s, 3H), 2.34 (s, 3H). 39

2-(2-chloro-6- fluorophenyl)-N- (6-methyl-2- morpholinopyrimidin- 4-yl)thiazolo[5,4- c]pyridin-4-amine 1 457.1 A 6.29 ¹H NMR (500 MHz, DMSO-d₆): δ 10.30 (s, 1H), 8.44 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 6.0 Hz,1H), 7.72-7.69 (m, 1H), 7.62-7.60 (m, 1H), 7.55-7.51 (m, 1H), 6.45 (s,1H), 3.55-3.54 (m, 8H), 2.22 (s, 3H). 40

2-(2-chloro-6- fluorophenyl)-N- (6- morpholinopyrimidin- 4-yl)thiazolo[5,4- c]pyridin-4-amine 1 443.1 A 5.70 ¹H NMR (500 MHz, DMSO-d₆): δ 10.28 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.28 (s, 1H), 7.76 (d, J= 5.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.62-7.60 (m, 1H), 7.54-7.50 (m, 1H),7.04 (s, 1H), 3.70-3.68 (m, 4H), 3.54-3.52 (m, 4H). 41

2-(4-(6-(2-(2- chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)-2- methylpyrimidin-4- yl)piperazin-1- yl)ethanol 1 500.2 A 5.23¹H NMR (500 MHz, DMSO- d₆): δ 10.14 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H),7.74 (d, J = 5.5 Hz, 1H), 7.73-7.70 (m, 1H), 7.61-7.60 (m, 1H),7.53-7.50 (m, 1H), 6.71 (s, 1H), 6.71 (s, 1H), 4.45 (t, J = 5.5 Hz, 1H),3.55-3.52 (m, 6H), 2.51-2.47 (m, 4H), 2.44-2.41 (m, 2H), 2.32 (s, 3H) 42

2-(4-(6-(2-(2- chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4-yl)piperazin-1- yl)ethanol 1 486.1 A 4.90 ¹H NMR(500 MHz, DMSO- d₆): δ 10.21 (s, 1H), 8.90 (d, J = 5.5 Hz, 1H), 8.26 (s,1H), 7.75 (d, J = 5.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.61-7.60 (m, 1H),7.53-7.50 (m, 1H), 7.00 (s, 1H), 4.46 (t, J = 5.5 Hz, 1H), 3.55-3.52 (m,6H), 2.50-2.47 (m, 4H), 2.44-2.42 (m, 2H). 43

2-((6-(2-(2-chloro- 6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4- yl)(methyl)amino) ethanol 1 431.1 A 5.01 ¹H NMR(500 MHz, DMSO- d₆): δ 10.15 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.22 (s,1H), 7.74 (d, J = 5.5 Hz, 1H), 7.71-7.68 (m, 1H), 7.61-7.60 (m, 1H),7.53-7.50 (m, 1H), 6.84 (s, 1H), 4.76 (s, 1H), 3.58 (s, 4H), 3.58 (s,3H). 44

2,2′-(6-(2-(2- chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4- ylazanediyl)diethanol 1 461.1 A 4.60 ¹H NMR (500MHz, DMSO- d₆): δ 10.11 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.21 (s, 1H),7.73 (d, J = 5.5 Hz, 1H), 7.71-7.68 (m, 1H), 7.61-7.59 (m, 1H),7.53-7.49 (m, 1H), 6.88 (s, 1H), 4.82 (s, 2H), 3.60 (s, 8H). 45

(6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4-yl)methanol 1 388.0 A 4.57 ¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (s, 1H), 8.63 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 7.86 (d, J= 5.5 Hz, 1H), 7.76-7.70 (m 2H) 7.62-7.60 (m, 1H), 7.54-7.51 (m, 1H),4.58 (t, J = 6.0 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H) 46

1-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4-yl)ethane-1,2- diol 1 434.0 A 4.46 ¹H NMR (500 MHz,DMSO- d₆): δ 10.72 (s, 1H), 8.65 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 7.85(d, J = 5.5 Hz, 1H), 7.78 (s, 1H), 7.74-7.73 (m, 2H), 7.69-7.65 (m, 1H),7.54-7.51 (m, 1H), 5.58-5.57 (m, 1H), 4.77-4.75 (m, 1H), 4.50-4.47 (m,1H), 3.75-3.71 (m, 1H), 3.54-3.49 (m, 1H) 47

2-(6-(2-(2-chloro- 6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4-ylamino)ethanol 1 417.0 A 4.63 ¹H NMR (500 MHz,DMSO- d₆): δ 10.10 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.17 (s, 1H),7.73-7.50 (m, 4H), 7.27 (br, 1H), 6.92 (br, 1H), 4.74 (s, 1H), 3.53 (m,2H), 3.34 (m, 2H). 48

N-(2-(2- chlorophenyl)thiazolo [5,4-c]pyridin- 4- yl)cyclopropane-carboxamide 1 330.0 A 5.81 ¹H NMR (500 MHz, DMSO- d₆): δ 11.36 (s, 1H),8.43 (d, J = 5.0 Hz, 1H), 8.22 (m, 1H), 7.90 (d, J = 5.0 Hz, 1H),7.74-7.56 (m, 3H), 2.09 (m, 1H), 0.91 (m, 4H). 49

2-(2-chloro-6- fluorophenyl)-N- (6- methylpyrimidin-4- yl)thiazolo[5,4-c]pyridin-4-amine 1 372.1 A 5.42 ¹H NMR (500 MHz, DMSO- d₆): δ 10.68 (s,1H), 8.63 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H),7.73-7.53 (m, 4H), 2.39 (s, 3H). 50

methyl 2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylcarbamate 1354.0 A 5.60 ¹H NMR (500 MHz, DMSO- d₆): δ 10.75 (br, 1H), 8.44 (d, J =6.5 Hz, 1H), 7.92 (d, J = 6.5 Hz, 1H), 7.75-7.69 (m, 3H), 3.73 (s, 3H).51

methyl 2-(2-chloro- 6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylcarbamate 1 338.0 A 5.33 ¹H NMR (500 MHz, DMSO- d₆): δ 10.83 (br, 1H),8.44 (d, J = 6.5 Hz, 1H), 7.93 (d, J = 6.5 Hz, 1H), 7.74-7.50 (m, 3H),3.73 (s, 3H). 52

N-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- yl)-2-hydroxyacetamide 1 338.1 A 4.50 ¹H NMR (500 MHz, DMSO- d₆): δ 8.48 (d, J= 6.5 Hz, 1H), 7.97 (d, J = 6.5 Hz, 1H), 7.73-7.50 (m, 3H), 5.75 (br,1H), 4.15 (s, 2H). 53

2-(2,6- dichlorophenyl)-N- (6- methylpyrimidin-4- yl)thiazolo[5,4-c]pyridin-4-amine 1 338.0 A 5. 70 ¹H NMR (500 MHz, DMSO- d₆): δ 10.67(br, 1H), 8.83 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 7.84 (d, J = 5.5 Hz,1H), 7.75-7.61 (m, 4H), 2.39 (s, 3H). 54

N-4-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-yl)pyrimidine-4,6- diamine 1 373.1 A 4.76 ¹H-NMR (500 MHz, DMSO- d₆): δ10.10 (br, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.11 (s, 1H), 7.73-7.521 (m,4H), 6.81 (s, 1H), 6.66 (br, 2H). 55

1-cyclopropyl-3-(2- (2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin-4-yl)urea 1 379.0 A 5.85 ¹H NMR (500 MHz, DMSO- d₆): δ 9.64 (s, 1H),8.32 (d, J = 6.0 Hz, 1H), 7.90 (m, 1H), 7.75-7.66 (m, 4H), 2.60 (m, 1H),0.69 (m, 2H), 0.50 (m, 2H). 56

2-(2-chlorophenyl)- N-(2,6- dimethylpyrimidin- 4-yl)thiazolo[5,4-c]pyridin-4-amine 1 368.0 A 5.91 ¹H NMR (500 MHz, DMSO- d₆): δ 10.55 (s,1H), 8.41 (d, J = 5.5 Hz, 1H), 8.29 (m, 1H), 7.79-7.59 (m, 4H), 7.30 (s,1H), 2.46 (s, 3H), 2.35 (s, 3H). 57

1-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-yl)-3-methylurea 1 337.1 A 5.15 ¹H NMR (500 MHz, DMSO- d₆): δ 9.84 (s,1H), 8.32 (d, J = 5.5 Hz, 1H), 7.95 (s, 1H), 7.74-7.51 (m, 4H), 2.78 (s,3H). 58

N-4-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-yl)-N6-methylpyrimidine- 4,6-diamine 1 403.0 A 5.44 ¹H NMR (500 MHz, DMSO- d₆):δ 10.11 (s, 1H), 8.37 (d, J = 5.0 Hz, 1H), 8.17 (s, 1H), 7.74-7.65 (m,4H), 7.18 (br, 1H), 6.89 (br, 1H), 2.78 (d, J = 4.5 Hz, 3H). 59

N-4-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- yl)-N6-methylpyrimidine- 4,6-diamine 1 387.1 A 5.22 ¹H NMR (500 MHz, DMSO- d₆):δ 10.11 (s, 1H), 8.37 (d, J = 5.0 Hz, 1H), 8.17 (s, 1H), 7.73-7.50 (m,4H), 7.17 (br, 1H), 6.84 (br, 1H), 2.78 (d, J = 5.0 Hz, 3H). 60

2-(2,6- dichlorophenyl)-N- (6- ((dimethylamino) methyl)pyrimidin-4-yl)thiazolo[5,4- c]pyridin-4-amine 1 431.0 A 5.50 ¹H NMR (500 MHz, DMSO-d₆): δ 10.73 (br, 1H), 8.68 (s, 1H), 8.48 (d, J = 6.0 Hz, 1H), 7.87 (d,J = 6.0 Hz, 1H), 7.76-7.69 (m, 4H), 3.40 (s, 2H), 2.26 (s, 6H). 61

2-(2-chloro-6- fluorophenyl)-N- (6- ((dimethylamino) methyl)pyrimidin-4-yl)thiazolo[5,4- c]pyridin-4-amine 1 415.1 A 5.29 ¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (s, 1H), 8.68 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 7.88 (d, J= 5.5 Hz, 1H), 7.74-7.53 (m, 4H), 3.40 (s, 2H), 2.26 (s, 6H). 62

N-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- yl)-2-(dimethylamino) acetamide 1 365.0 A 5.67 ¹H NMR (500 MHz, DMSO- d₆): δ10.64 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 7.98 (d, J = 5.5 Hz, 1H),7.75-7.51 (m, 3H), 3.26 (s, 2H), 2.35 (s, 6H). 63

6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidine- 4-carbonitrile 1 383.1 A 6.06 ¹H NMR (500 MHz, DMSO-d₆): δ 11.43 (s, 1H), 8.90 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.28 (s,1H), 7.96 (d, J = 5.0 Hz, 1H), 7.75-7.52 (m, 3H). 64

N-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4-yl)acetamide 1 431.1 A 5.30 ¹H NMR (500 MHz, DMSO-d₆): δ 10.67 (s, 1H), 8.50 (s, 1H), 8.45 (d, J = 6.0 Hz, 1H), 8.29 (s,1H), 7.86 (d, J = 6.0 Hz, 1H), 7.76-7.67 (m, 3H), 2.14 (s, 3H). 65

2-amino-N-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin-4-yl)acetamide 1 353.0 A 4.51 ¹H NMR (500 MHz, DMSO- d₆): δ 8.45 (d, J =6.0 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.74-7.66 (m, 3H), 5.13 (br, 2H),3.39 (s, 2H). 66

2-amino-N-(2-(2- chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-yl)acetamide 1 337.1 A 4.24 ¹H NMR (500 MHz, DMSO- d₆): δ 8.45 (d, J =6.0 Hz, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.73-7.50 (m, 3H), 5.12 (br, 2H),3.40 (s, 2H). 67

2-(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4-yl)prop an-2-ol 1 432.0 A 5.53 ¹H NMR (500 MHz,DMSO- d₆): δ 8.66 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 7.87-7.67 (m, 5H),5.33 (s, 1H), 1.42 (s, 6H). 68

2-(6-(2-(2-chloro- 6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4-yl)propan-2-ol 1 416.1 A 5.29 ¹H NMR (500 MHz,DMSO- d₆): δ 8.66 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7.86-7.53 (m, 5H),5.33 (s, 1H), 1.42 (s, 6H). 69

3-amino-N-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin-4-yl)propanamide 1 367.1 A 4.26 ¹H NMR (500 MHz, DMSO- d₆): δ 8.44 (d, J= 5.5 Hz, 1H), 7.92 (d, J = 5.5 Hz, 1H), 7.74-7.66 (m, 3H), 2.89 (m,2H), 2.51 (m, 2H). 70

1-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-yl)-3-methylurea 1353.1 B 5.41 ¹H NMR (500 MHz, DMSO- d₆): δ 8.31 (d, J = 6.0 Hz, 1H),7.95 (m, 1H), 7.74-7.72 (m, 3H), 7.68-7.66 (m, 1H), 2.76 (d, J = 5.0 Hz,3H). 71

3-amino-N-(2-(2- chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-yl)propanamide 1 351.0 A 4.45 ¹H NMR (500 MHz, DMSO- d₆): δ 8.44 (d, J =5.5 Hz, 1H), 7.92 (d, J = 5.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.60 (d, J =8.5 Hz, 1H), 7.53-7.49 (m, 1H), 5.00 (br, 2H), 2.88 (t, J = 6.0 Hz, 2H),2.54-2.52 (m, 2H). 72

6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)-N-methylpyrimidine- 4-carboxamide 1 431.1 B 5.51 ¹H NMR (500 MHz, DMSO-d₆): δ 11.13 (br, 1H), 8.89 (d, J = 5.5 Hz, 1H), 8.84 (d, J = 1.0 Hz,1H), 8.51 (d, J = 5.5 Hz, 1H), 8.23 (s, 1H), 7.90 (d, J = 5.5 Hz, 1H),7.75-7.66 (m, 3H), 2.83 (d, J = 5.0 Hz, 3H). 73

(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidin- 4- yl)(morpholino) methanone 1 487.0 A 5.16 ¹H NMR(500 MHz, DMSO- d₆): δ 10.97 (s, 1H), 8.80 (s, 1H), 8.49 (d, J = 5.5 Hz,1H), 7.76-7.74 (m, 2H), 7.70-7.68 (m, 1H), 3.68-3.64 (m, 4H), 3.58-3.60(m, 2H), 3.45-3.44 (m, 2H). 74

6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- ylamino)-N-methylpyrimidine- 4-carboxamide 1 415.1 B 5.28 ¹H NMR (500 MHz, DMSO-d₆): δ 10.93 (s, 1H), 8.89-8.84 (m, 2H), 8.52 (m, 1H), 8.21 (s, 1H),7.93 (m, 1H), 7.74-7.51 (m, 3H), 2.82 (d, J = 5.0 Hz, 3H). 75

(2-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyridin-4- yl)methanol 1 387.0 A 5.16 ¹H NMR (500 MHz, DMSO-d₆): δ 10.18 (s, 1H), 8.34 (d, J = 5.0 Hz), 8.16 (d, J = 5.0 Hz),7.71-7.49 (m, 5H), 6.90 (d, J = 5.0 Hz), 5.43 (t, J = 5.0 Hz, 1H), 4.53(d, J = 5.5 Hz, 2H). 76

2-(2,6- dichlorophenyl)-N- (4-methylpyridin-2- yl)thiazolo[5,4-c]pyridin-4-amine 1 387.1 B 6.89 ¹H NMR (500 MHz, DMSO- d₆): δ 10.12 (s,1H), 8.35 (d, J = 5.0 Hz), 8.11 (d, J = 5.0 Hz), 7.73-7.66 (m, 4H), 7.47(s, 1H), 6.82 (d, J = 5.0 Hz, 1H), 2.31 (s, 3H). 77

N-(4- (aminomethyl) pyrimidin-2-yl)-2-(2,6- dichlorophenyl)thia-zolo[5,4-c]pyridin- 4-amine 1 403.1 B 4.58 ¹H NMR (500 MHz, DMSO- d₆): δ8.60 (br, 1H), 8.45 (d, J = 5.5 Hz), 7.85 (d, J = 5.0 Hz), 7.75-7.69 (m,4H), 3.73 (br, 2H). 78

N-(4- (aminomethyl) pyrimidin-2-yl)-2-(2- chloro-6-fluorophenyl)thiazolo [5,4-c]pyridin-4- amine 1 387.1 B 4.39 ¹H NMR (500MHz, DMSO- d₆): δ 8.64 (s, 1H) 8.46 (d, J = 5.5 Hz), 7.85 (d, J = 5.0Hz), 7.72-7.51 (m, 4H), 3.72 (br, 2H). 79

6-[2-(2,6-Dichloro- 4-cyano-phenyl)- thiazolo[5,4- c]pyridine-4-ylamino]- nicotinonitrile 2 423 C 4.70 ¹H NMR (400 MHz, DMSO- d₆): δ10.94 (br s, 1H), 8.70 (dd, J = 2.3, 0.8 Hz, 1H), 8.45 (d, J = 5.6 Hz,1H), 8.39 (s, 2H), 8.13 (dd, J = 8.8, 2.3 Hz, 1H), 7.85 (d, J = 5.6 Hz,1H), 7.82 (d, J = 8.9 Hz, 1H). 80

3,5-Dichloro-4-[4- (2,6-dimethyl- pyrimidin-4- ylamino)- thiazolo[5,4-c]pyridine-2-yl]- benzonitrile 2 427 C 3.25 ¹H NMR (400 MHz, DMSO- d₆):δ 10.63 (br s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.38 (s, 2H), 7.83 (d, J =5.6 Hz, 1H), 7.24 (s, 1H), 2.43 (s, 3H), 2.34 (s, 3H). 81

Cyclopropane- carboxylic acid [2-(2,6- dichloro-4-cyano- phenyl)-thiazolo[5,4- c]pyridin-4-yl]- amide 2 389 C 4.58 ¹H NMR (400 MHz, DMSO-d₆): δ 11.44 (br s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.36 (s, 2H), 7.92(d, J = 5.5 Hz, 1H), 2.07- 1.99 (m, 1H), 0.89-0.79 (m, 4H). 82

3,5-Dichloro-4-[4- (pyrimidin-4- ylamino)- thiazolo[5,4-c]pyridin-2-yl]- benzonitrile 2 399 C 3.55 ¹H NMR (400 MHz, DMSO- d₆): δ10.82 (br s, 1H), 8.76 (d, J = 1.2 Hz, 1H), 8.52 (d, J = 5.9 Hz, 1H),8.47 (d, J = 5.6 Hz, 1H), 8.39 (s, 2H), 7.87 (d, J = 5.6 Hz, 1H), 7.76(dd, J = 5.9, 1.3 Hz, 1H). 83

3,5-Dichloro-4-[4- (6-methyl- pyrimidin-4- ylamino)- thiazolo[5,4-c]pyridin-2-yl]- benzonitrile 2 413 C 3.47 ¹H NMR (400 MHz, DMSO- d₆): δ10.69 (br s, 1H), 8.62 (d, J = 1.2 Hz, 1H), 8.46 (d, J = 5.6 Hz, 1H),8.38 (s, 2H), 7.84 (d, J = 5.6 Hz, 1H), 7.57 (s, 1H), 2.39 (s, 3H). 84

1-[2-(2,6,- Dichloro-4-cyano- phenyl)- thiazolo[5,4- c]pyridine-4-yl]-3-methyl-urea 2 378 C 4.12 ¹H NMR (400 MHz, CDCl₃): δ 8.27 (s, 1H), 7.78(s, 2H), 7.70 (d, J = 5.8 Hz, 1H), 3.02 (d, J = 4.6 Hz, 3H). 85

3,5-Dichloro-4-[4- (6-morpholin-4-yl- pyrimidin-4- ylamino)-thiazolo[5,4- c]pyridine-2-yl]- benzonitrile 2 484 C 3.52 ¹H NMR (400MHz, DMSO- d₆): δ 10.30 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.38 (s, 2H),8.28 (d, J = 0.9 Hz, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.01 (br s, 1H),3.69 (t, J = 4.8 Hz, 4H), 3.53 (t, J = 4.7 Hz, 4H). 86

3,5-Dichloro-4-(4- {6-(2-hydroxy- ethyl)-piperazin-1- yl]-pyrimidin-4-ylamino}- thiazolo[5,4- c]pyridine-2-yl)- benzonitrile 2 527 C 2.70 ¹HNMR (400 MHz, DMSO- d₆): δ 10.23 (br s, 1H), 8.40 (d, J = 5.6 Hz, 1H),8.37 (s, 2H), 8.25 (s, 1H), 7.75 (d, J = 5.6 Hz, 1H), 6.97 (s, 1H), 4.44(br s, 1H), 3.53-3.52 (m, 8H), 2.43- 2.40 (m, 4H). 87

3,5-Dichloro-4-[4- (5-hydroxymethyl- pyrimidin-4- ylamino)-thiazolo[5,4- c]pyridine-2-yl}- benzonitrile 2 429 C 3.35 ¹H NMR (400MHz, DMSO- d₆): δ 10.76 (s, 1H), 8.62 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H),8.38 (s, 2H), 7.85 (d, J = 5.6 Hz, 1H), 7.74 (s, 1H), 5.56 (t, J = 5.8Hz, 1H), 4.48 (d, J = 5.7 Hz, 2H). 88

3,5-Dichloro-4-[4- (4-hydroxymethyl- pyridin-2-ylamino)- thiazolo[5,4-c]pyridin-2-yl]- benzonitrile 2 462 C 3.13 ¹H NMR (400 MHz, DMSO- d₆): δ8.52 (d, J = 5.9 Hz, 1H), 8.43 (s, 2H), 8.38 (d, J = 6.2 Hz, 1H), 7.99(d, J = 5.9 Hz, 1H), 7.86 (s, 1H), 7.28 (d, J = 6.2 Hz 1H), 4.70 (s,2H). 89

3,5-Dichloro-4-[4- (6-dimethylamino- methyl-pyrimidin-4-ylamino)-thiazolo [5,4-c]pyridin-2- yl]-benzonitrile 2 456 C 3.01 ¹H NMR(400 MHz, DMSO- d₆): δ 10.73 (s, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.46 (d,J = 5.6 Hz, 1H), 8.38 (s, 2H), 7.85 (d, J = 5.6 Hz, 1H), 7.69 (br s,1H), 3.45 (s, 2H), 2.24 (s, 6H). 90

6-[2-(2,6-Dichloro- 4-cyano-phenyl)- thiazolo[5,4- c]pyridin-4-ylamino]- pyrimidine-4- carboxylic acid amide 2 442 C 3.88 ¹H NMR (400MHz, DMSO- d₆): δ 11.10 (s, 1H), 8.83 (d, J = 1.2 Hz, 1H), 8.51 (d, J =5.6 Hz, 1H), 8.39 (s, 2H), 8.24 (d, J = 1.2 Hz, 1H), 8.18 (s, 1H), 7.91(d, J = 5.6 Hz, 1H), 7.87 (s, 1H). 91

N-{6-[2-(2,6- Dichloro-4-cyano- phenyl)- thiazolo[5,4- c]pyridin-4-ylamino]- pyrimidin-4-yl}- acetamide 2 456 C 3.75 ¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 10.64 (s, 1H), 8.47 (d, J = 1.1 Hz, 1H), 8.43 (d,J = 5.6 Hz, 1H), 8.38 (s, 2H), 8.25-8.23 (m, 1H), 7.84 (d, J = 5.6 Hz,1H), 2.11 (s, 3H). 92

3,5-Dichloro-4-[4- (5-hydroxymethyl- pyridin-2-ylamino)- thiazolo[5,4-c]pyridin-2-yl]- benzonitrile 2 428 C 3.06 ¹H NMR (400 MHz, DMSO- d₆): δ10.23 (s, 1H), 8.37 (s, 2H), 8.33 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 2.2Hz, 1H), 7.65-7.64 (m, 3H), 5.16 (t, J = 5.5 Hz, 1H), 4.45 (d, J = 5.2Hz, 2H). 93

3,5-Dichloro-4-[4- (6-methoxy- pyrimidin- 4-ylamino)- thiazolo[5,4-c]pyridin- 2-yl]- benzonitrile 2 429 C 4.69 ¹H NMR (400 MHz, DMSO- d₆):δ 10.67 (s, 1H), 8.49 (d, J = 0.9 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H),8.39 (s, 2H), 7.81 (d, J = 5.6 Hz, 1H), 7.33-7.30 (s, 1H), 3.91 (s, 3H).94

3,5-Dichloro-4-[4- (5-methyl-pyrazin- 2-ylamino)- thiazolo[5,4-c]pyridin- 2-yl]-benzonitrile 2 413 C 4.09 ¹H NMR (400 MHz, DMSO- d₆): δ10.42 (s, 1H), 9.07 (s, 1H), 8.38 (s, 2H), 8.36 (d, J = 5.7 Hz, 1H)8.22-8.20 (m, 1H), 7.72 (d, J = 5.6 Hz, 1H), 2.44 (s, 3H). 95

3,5-Dichloro-4-[4- (6-methyl-pyridazin- 3-ylamino)- thiazolo[5,4-c]pyridin- 2-yl]-benzonitrile 2 413 C 3.57 ¹H NMR (400 MHz, DMSO- d₆): δ10.60 (s, 1H), 8.38 (s, 2H), 8.34 (d, J = 5.6 Hz, 1H), 7.98-7.90 (m,1H), 7.72 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 2.53 (s, 3H).96

[2-(2,6-Dichloro-4- cyano-phenyl)- thiazolo[5,4- c]pyridin-4-yl]-carbamic acid methyl ester 2 379 C 4.37 ¹H NMR (400 MHz, CDCl₃): δ 8.45(s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.76 (s,2H), 3.87 (s, 3H). 97

3,5-Dichloro-4-[4- (6-methylamino- pyrimidin-4- ylamino)-thiazolo[5,4-c] pyridin-2-yl]- benzonitrile 3 428 C 3.32 ¹H NMR (400MHz, DMSO- d₆): δ 10.13 (s, 1H), 8.39-8.35 (m, 3H), 8.17 (s, 1H), 7.73(d, J = 5.6 Hz, 1H), 7.16 (s, 1H), 6.79 (s, 1H), 2.78 (d, J = 4.7 Hz,3H). 98

4-[4-(6-Amino- pyrimidin-4- ylamino)- thiazolo[5,4- c]pyridin-2-yl]-3,5-di- chloro-benzonitrile 3 414 C 3.18 ¹H NMR (400 MHz, DMSO- d₆): δ 8.52(s, 1H), 8.49 (d, J = 5.7 Hz, 1H), 8.41 (s, 2H), 7.95 (d, J = 5.7 Hz,1H). 99

3,5-Dichloro-4-{4- [6-(2-hydroxy-2- methyl- propylamino)-pyrimidin-4-yl- amino]-thiazolo[5,4- c]pyridin-2-yl}- benzonitrile 3 486C 3.33 ¹H NMR (400 MHz, DMSO- d₆): δ 10.12 (s, 1H), 8.40-8.36 (m, 3H),8.15 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.12 (br s, 1H), 6.94 (br s,1H), 4.57 (s, 1H), 3.31-3.24 (m, 2H), 1.11 (s, 6H). 100

3-Chloro-4-[4-(2,6- dimethyl-pyrimidin- 4-ylamino)- thiazolo[5,4-c]pyridin- 2-yl]-5-fluoro- benzonitrile 4 411 C 3.11 ¹H NMR (400 MHz,DMSO- d₆): δ 8.61 (d, J = 5.6 Hz, 1H), 8.30 (t, J = 1.2 Hz, 1H), 8.24(dd, J = 9.1, 1.4 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.59 (br s, 1H),2.65 (s, 3H), 2.56 (s, 3H). 101

1-[2-(2-Chloro-4- cyano-6-fluoro-phen- yl)-thiazolo[5,4-c]pyridin-4-yl]-3- methyl-urea 4 362 C 3.94 ¹H NMR (400 MHz, DMSO- d₆):δ 9.82 (s, 1H), 8.31 (d, J = 5.7 Hz, 1H), 8.26 (t, J = 1.3 Hz, 1H), 8.20(dd, J = 9.0, 1.5 Hz, 1H), 7.75-7.70 (m, 2H), 2.75 (d, J = 4.6 Hz, 3H).102

2-(2,6- dichlorophenyl)-N- (pyrimidin-4- yl)thiazolo[4,5- d]pyrimidin-7-amine 5 374.9 B 3.84 ¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H), 8.91 (d,J = 14.7 Hz, 2H), 8.63 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 5.8 Hz, 1H),7.79-7.72 (m, 2H), 7.68 (dd, J = 9.3, 6.7 Hz, 1H). 103

2-(2,6- dichlorophenyl)-N- (2,6- dimethylpyrimidin- 4-yl)thiazolo[4,5-d]pyrimidin-7- amine 5 403.00 B 3. 55 ¹H NMR (400 MHz, DMSO-d₆) δ 11.26(s, 1H), 8.92 (s, 1H), 7.78-7.71 (m, 2H), 7.68 (dd, J = 9.3, 6.7 Hz,1H), 7.41 (s, 1H), 2.35 (s, 3H), 2.39 (s, 3H). 104

[2-(2,6- dichlorophenyl)-N- (6- methylpyrimidin-4- yl)thiazolo[4,5-d]pyrimidin-7- amine 5 389.0 B 3. 79 ¹H NMR (400 MHz, DMSO-d₆) δ 11.35(s, 1H), 8.92 (s, 1H), 8.77 (d, J = 0.8 Hz, 1H), 7.78(7.72 (m, 2H),7.71(7.61 (m, 2H), 2.44 (s, 3H). 105

2-(4-(6-(2-(2,6- dichlorophenyl)thia- zolo[4,5- d]pyrimidin-7-ylamino)pyrimidin- 4-yl)piperazin-1- yl)ethanol 5 503.1 B 3.35 ¹H NMR(400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.86 (s, 1H), 8.35 (s, 1H),7.78-7.71 (m, 2H), 7.67 (dd, J = 9.3, 6.7 Hz, 1H), 6.94 (s, 1H), 4.45(t, J = 5.4 Hz, 1H), 3.65-3.47 (m, 6H), 3.33 (m, 4H), 2.43 (t, J = 6.2Hz, 2H). 106

3-Chloro-5-fluoro- 4-[4-(6- hydroxymethyl- pyrimidin-4- ylamino)-thiazolo[5,4- c]pyridin-2-yl]- benzonitrile 4 413 C 3.17 ¹H NMR (400MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.62 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H),8.28 (s, 1H), 8.22 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 7.74(s, 1H), 5.56 (t, J = 5.8 Hz, 1H), 4.48 (d, J = 5.8 Hz, 2H). 107

(6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4- yl)(morpholino) methanone 1 471.0 A 4.99 ¹H-NMR(500 MHz, DMSO- d₆): δ 11.03 (br, 1H), 8.80 (s, 1H), 8.50 (d, J = 6.0Hz, 1H), 7.89 (s, 2H), 7.74-7.52 (m, 3H), 3.68-3.65 (m, 4H), 3.58-3.32(m, 4H) 108

2-(2-chloro-6- fluorophenyl)-N- (pyridin-2- yl)thiazolo[5,4-c]pyridin-4-amine 1 357.1 B 6.29 ¹H-NMR (500 MHz, DMSO- d₆): δ 10.19 (s,1H), 8.35 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 4.5 Hz, 1H), 7.74-7.67 (m,4H), 7.53-7.50 (m, 2H), 6.98 (m, 1H) 109

2-(2-chloro-6- fluorophenyl)-N- (4-methylpyridin-2- yl)thiazolo[5,4-c]pyridin-4-amine 1 371.1 B 6.62 ¹H-NMR (500 MHz, DMSO- d₆): δ 10.12 (s,1H), 8.35 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 5.0 Hz, 1H), 7.71-7.45 (m,5H), 6.82 (d, J = 5.0 Hz, 1H), 2.31 (s, 3H) 110

2-(2,6- dichlorophenyl)-N- (pyridazin-3- yl)thiazolo[5,4-c]pyridin-4-amine 1 374.0 A 5.62 ¹H-NMR (500 MHz, DMSO- d₆): δ 10.69 (s,1H), 8.80 (s, 1H), 8.37 (d, J = 6.0 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H),7.75-7.61 (m, 5H) 111

6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyrimidine- 4-carboxamide 1 417.0 A 5.09 ¹H-NMR (500 MHz, DMSO-d₆): δ 11.02 (br, 1H), 8.83 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.26 (s,1H), 8.19 (s, 1H), 7.88 (m, 2H), 7.74-7.66 (m, 3H) 112

2-(2-chloro-6- fluorophenyl)-N- (pyridazin-3- yl)thiazolo[5,4-c]pyridin-4-amine 1 358.0 A 5.38 ¹H-NMR (500 MHz, DMSO- d₆): δ 10.70(br, 1H), 8.85 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.10 (d, J = 8.0 Hz,1H) 7.78-7.51 (m, 5H) 113

2-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)isonicotino- nitrite 1 398.1 B 6.72 ¹H-NMR (500 MHz, DMSO- d₆):δ 10.70 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 6.0 Hz, 1H),8.27 (s, 1H), 7.79-7.66 (m, 4H), 7.38 (m, 1H) 114

6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyridazine- 3-carboxamide 1 417.0 A 5.18 ¹H-NMR (500 MHz, DMSO-d₆): δ 11.06 (br, 1H), 8.43 (d, J = 5.5 Hz, 1H), 8.30 (m, 1H), 8.21 (d,J = 9.0 Hz, 1H), 8.13 (d, J = 4.5 Hz, 1H), 7.84 (d, J = 5.5 Hz, 1H),7.76-7.66 (m, 4H) 115

(6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)pyridazin- 3- yl)(morpholino) methanone 1 487.1 B 5. 35 ¹H-NMR(500 MHz, DMSO- d₆): δ 8.28 (d, J = 5.5 Hz, 1H), 8.11 (m, 1H), 7.72-7.54(m, 5H), 3.57 (s, 4H), 3.47 (s, 4H) 116

(6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyridazin- 3- yl)(morpholino) methanone 1 471.2 B 5.14 ¹H-NMR(500 MHz, DMSO- d₆): δ 10.95 (br, 1H), 8.40 (d, J = 5.5 Hz, 1H), 8.22(d, J = 8.0 Hz, 1H), 7.74-7.51 (m, 5H), 3.69 (s, 4H), 3.59 (s, 4H) 117

6-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)-N,N-dimethylpyridazine- 3-carboxamide 1 445.1 A 5.42 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.95 (br, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 6.0 Hz,1H), 7.80-7.66 (m, 5H), 3.07 (s, 3H), 3.06 (s, 3H) 118

6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- ylamino)-N,N-dimethylpyridazine- 3-carboxamide 1 429.0 A 5.42 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.95 (br, 1H), 8.41 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.80-7.51(m, 5H), 3.07 (s, 3H), 3.06 (s, 3H) 119

2-(2,6- dichlorophenyl)-N- (pyrazin-2- yl)thiazolo[5,4-c]pyridin-4-amine 1 374.0 A 5.72 ¹H-NMR (500 MHz, DMSO- d₆): δ 10.55 (s,1H), 9.18 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J =2.5 Hz, 1H), 7.78-7.66 (m, 4H) 120

2-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylamino)isonicotin- amide 1 416.1 B 5.04 ¹H-NMR (500 MHz, DMSO- d₆): δ10.37 (s, 1H), 8.39 (m, 2H), 8.15 (s, 1H), 8.06 (s, 1H), 7.75-7.67 (m,5H), 7.34 (m, 1H) 121

6-(2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyridazine- 3-carboxamide 1 401.0 A 4.90 ¹H-NMR (500 MHz, DMSO-d₆): δ 11.05 (br, 1H), 8.42-8.13 (m, 4H), 7.84-7.53 (m, 5H) 122

N-(6- (aminomethyl) pyrimidin-4-yl)-2-(2- chloro-6-fluorophenyl)thiazolo [5,4-c]pyridin-4- amine 1 387.1 B 4.42 ¹H-NMR (500MHz, DMSO- d₆): δ 8.64 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.85 (d, J =5.0 Hz, 1H), 7.73-7.70 (m, 2H), 7.62-7.51 (m, 2H), 3.73 (s, 2H) 123

2-(2-chloro-6- fluorophenyl)-N- (pyrazin-2- yl)thiazolo[5,4-c]pyridin-4-amine 1 358.0 A 5.46 ¹H-NMR (500 MHz, DMSO- d₆): 10.56 (s,1H), 9.16 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.21 (s, 1H),7.78-7.53 (m, 4H) 124

5-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4- ylamino)pyrazine-2-carboxamide 1 417.1 B 5.32 ¹H-NMR (500 MHz, DMSO- d₆): δ 11.06 (br,1H), 9.11 (s, 1H), 8.81 (s, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H),7.81-7.58 (m, 5H) 125

isopropyl 2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylcarbamate1 382.1 B 6.62 ¹H-NMR (500 MHz, DMSO- d₆): δ 10.67 (br, 1H), 8.43 (d, J= 5.5 Hz, 1H), 7.91 (d, J = 5.5 Hz, 1H), 7.74-7.61 (m, 3H), 4.93 (m,1H), 1.29 (d, J = 6.5 Hz, 6H) 126

1-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-yl)-3-(2-hydroxyethyl)urea 1 383.1 B 4.74 ¹H-NMR (500 MHz, DMSO- d₆): δ 9.78 (br,1H), 8.32 (d, J = 5.5 Hz, 1H), 8.03 (s, 1H), 7.74-7.65 (m, 4H), 4.82 (s,1H), 3.52 (m, 2H), 3.28 (m, 2H)

Method F: Experiments performed on a VG Platform II quadrupole massspectrometer linked to a Hewlett Packard HP1050 LC system with diodearray detector and 100 position autosampler., using a Phenomenex Luna 3μm C₁₈(2) 30×4.6 mm and a 2 mL/minute flow rate. The mobile phaseconsisted of formic acid 0.1% in water (solvent A) and formic acid 0.1%in acetonitrile (solvent B). The initial solvent system was 95% solventA and 5% solvent B for the first 0.3 minute followed by a gradient up to5% solvent A and 95% solvent B over the next 4 minutes. The finalsolvent system was held constant for a further 1 minute.

Example 1274-[4-(6-Amino-2-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-benzonitrilehydrochloride salt

Step 1. (6-Chloro-2-methylpyrimidin-4-yl)-bis-carbamic acid tert-butylester

To a solution of 6-chloro-2-methylpyrimidin-4-ylamine (1.36 g, 9.48mmol) in THF (40 mL) under a nitrogen atmosphere was added di-tert-butyldicarbonate (4.15 g, 18.95 mmol) followed by DMAP (166 mg, 0.95 mmol).The reaction mixture was stirred at room temperature for 3 hours and wasthen partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc (×2) and the combined organic phases were washedwith brine, dried (MgSO₄) and concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 0-10% EtOAc in cyclohexane to afford the title compound asa white solid (2.4 g, 73% yield). LCMS (Method D): RT=4.43 min, m/z: 344[M+H⁺].

Step 2.{6-[2-(2,6-Dichloro-4-cyanophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-2-methylpyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of4-(4-aminothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.102g, 0.318 mmol), (6-chloro-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (0.126 g, 0.365 mmol), Pd₂(dba)₃ (0.015 g, 0.016 mmol),XantPhos (0.018 g, 0.032 mmol) and Cs₂CO₃ (0.259 g, 0.795 mmol) indioxane (3 mL) was degassed with a stream of argon. The reaction mixturewas heated at 80° C. for 1 hour in a sealed vial. After cooling to roomtemperature, the crude mixture was filtered through Celite® washing withEtOAc and the filtrate concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 0-30% EtOAc in cyclohexane to afford the title compound asa yellow glass (58 mg, 29% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.44 (d,J=5.6 Hz, 1H), 7.97 (s, 1H), 7.80-7.73 (m, 3H), 7.70 (s, 1H), 2.52 (s,3H), 1.53 (s, 18H).

Step 3.4-[4-(6-Amino-2-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3,5-dichlorobenzonitrilehydrochloride salt

A mixture of{6-[2-(2,6-dichloro-4-cyanophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-2-methylpyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (0.058 g, 0.092 mmol) in HCl (4N in dioxane, 1 mL)was heated at 50° C. for 2 hours in a sealed vial. After cooling to roomtemperature, the crude reaction mixture was filtered through a PTFEfilter. The resultant solid was washed with EtOAc and dried underreduced pressure to afford the title compound as a pink solid (38 mg,89% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.40 (s, 1H), 8.51 (d, J=5.7Hz, 1H), 8.41 (s, 2H), 7.95 (d, J=5.7 Hz, 1H), 7.14 (s, 1H), 2.49 (s,3H). LCMS (Method C): RT=3.23 min, m/z: 428 [M+H⁺].

Example 1283,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

A mixture of4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.095g, 0.25 mmol), 6-ethylpyrimidin-4-ylamine (29 mg, 0.23 mmol), Pd₂(dba)₃(11 mg, 0.012 mmol), XantPhos (14 mg, 0.025 mmol) and cesium carbonate(0.201 g, 0.62 mmol) in dioxane (2.5 mL) was degassed with a stream ofnitrogen. The reaction mixture was heated at 70° C. for 16 hours. Aftercooling to room temperature, the resultant mixture was diluted withwater and filtered through Celite® washing with DCM. The aqueous phasewas further extracted with DCM and the combined organic layers weredried (MgSO₄) and concentrated under reduced pressure. The resultantresidue was purified by silica gel flash C₁₈ column chromatographyeluting with 0-100% EtOAc in pentane followed by a 20-60% gradient MeOHin H₂O +1M HCl (1.25 mL in each 25 mL of eluent). The product containingfractions were combined and concentrated under reduced pressure. Theresultant solid was suspended in a mixture DCM/EtOAc/MeOH and washedwith a saturated solution of NaHCO₃, then dried and concentrated underreduced pressure. Further column chromatography purification on silicagel, eluting with 0-50% EtOAc in DCM, afforded the title compound as apale yellow solid (30 mg, 28% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.70(br s, 1H), 8.66 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.39 (s,2H); 7.84 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.67 (q, J=7.6 Hz, 2H), 1.23(t, J=7.6 Hz, 3H). LCMS (Method C): RT=3.81 min, m/z: 427 [M+H⁺].

Example 1293,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzamide

The column from which3,5-dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrilewas isolated was then further eluted with 0-10% MeOH in DCM to affordthe title compound as a yellow solid (8 mg, 7% yield). ¹H NMR (300 MHz,DMSO-d₆): δ 10.65 (s, 1H), 8.65 (d, J=1.2 Hz, 1H), 8.45 (d, J=5.6 Hz,1H), 8.32 (br s, 1H), 8.13 (s, 2H), 7.86-7.80 (m, 2H), 7.56 (s, 1H),2.66 (q, J=7.6 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H). LCMS (Method C): RT=2.95min, m/z: 445 [M+H⁺].

Example 1304-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3-chloro-5-fluorobenzonitrilehydrochloride salt

Step 1.[2-(2-Chloro-4-cyano-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester

A mixture of4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile(0.118 g, 0.320 mmol) carbamic acid tert-butyl ester (0.187 g, 1.60mmol), Pd₂(dba)₃ (0.015 g, 0.016 mmol), XantPhos (0.019 g, 0.032 mmol)and potassium phosphate tribasic (0.136 g, 0.64 mmol) in toluene (2.0mL) and water (0.3 mL) was degassed with a stream of argon. The reactionmixture was heated at 60° C. for 4 hours. After cooling to roomtemperature, the crude mixture was filtered through Celite® washing withEtOAc and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 0-20% EtOAc in cyclohexane to afford the title compound asa yellow solid (173 mg, quantitative). ¹H NMR (400 MHz, CDCl₃): δ 8.35(d, J=5.6 Hz, 1H), 7.86 (s, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.68 (t, J=1.4Hz, 1H), 7.47 (dd, J=8.1, 1.5 Hz, 1H), 1.56 (s, 9H).

Step 2.4-(4-Aminothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile

A mixture of[2-(2-chloro-4-cyano-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester (0.320 mmol) in HCl (4N in dioxane, 2.5 mL) washeated at 50° C. for 3 hours in a sealed vial. After cooling to roomtemperature, the volatiles were removed under reduced pressure and theresultant residue was partitioned between EtOAc and a saturated solutionof NaHCO₃. The aqueous phase was extracted with EtOAc, and the combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentratedto dryness under reduced pressure to afford the title compound as ayellow solid (76 mg, 78% yield over two steps). ¹H NMR (400 MHz, CDCl₃):δ 8.21 (d, J=5.8 Hz, 1H), 7.69 (t, J=1.4 Hz, 1H), 7.53-7.46 (m, 2H),4.84 (s, 2H).

Step 3.{6-[2-(2-Chloro-4-cyano-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of4-(4-aminothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile(0.068 g, 0.224 mmol), (6-chloropyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (0.085 g, 0.257 mmol), XantPhos (0.013 g, 0.022 mmol)and Cs₂CO₃ (0.182 g, 0.56 mmol) in dioxane (2.5 mL) was degassed with astream of argon. Pd₂(dba)₃ (0.010 g, 0.011 mmol) was added and thereaction mixture was heated at 80° C. for 1 hour. After cooling to roomtemperature, the crude reaction mixture was filtered through Celite®,washing with EtOAc, and the filtrate was concentrated under reducedpressure. The resultant residue was purified by column chromatography onsilica gel eluting with 0-30% EtOAc in cyclohexane to afford the titlecompound as a yellow oil (58 mg, 43% yield). ¹H NMR (400 MHz, CDCl₃): δ8.60 (s, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.29 (s, 1H), 7.87 (s, 1H), 7.78(d, J=5.6 Hz, 1H), 7.70 (t, J=1.4 Hz, 1H), 7.50 (dd, J=8.2, 1.5 Hz, 1H),1.54 (s, 18H).

Step 4.4-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3-chloro-5-fluorobenzonitrilehydrochloride salt

A mixture of{6-[2-(2-chloro-4-cyano-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (0.058 g, 0.097 mmol) in HCl (1.25N inisopropanol, 2 mL) was heated at 45° C. for 24 hours. After cooling toroom temperature, the crude reaction mixture was filtered and theresultant solid was washed with isopropanol and then dried under reducedpressure. The solid thus obtained was sonicated in isopropanol for 1hour, then filtered and dried under reduced pressure to afford the titlecompound as a yellow solid (35 mg, 91% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 11.48 (s, 1H), 8.52-8.46 (m, 2H), 8.32-8.6 (m, 3H), 7.94 (d,J=5.7 Hz, 1H), 6.97 (s, 2H). LCMS (Method C): RT=3.04 min, m/z: 398[M+H⁺].

Example 131N-[2-(4-Amino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diaminehydrochloride salt

Step 1.[3,5-Dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-carbamicacid tert-butyl ester

A mixture of4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.40 g,0.905 mmol), carbamic acid tert-butyl ester (0.159 g, 1.36 mmol),XantPhos (0.053 g, 0.091 mmol) and K₃PO₄ (0.384 g, 1.81 mmol) in toluene(9 mL) and water (1.5 mL), was degassed with a stream of argon.Pd₂(dba)₃ (0.041 g, 0.045 mmol) was then added and the reaction mixturewas heated at 85° C. for 2 hours using microwave irradiation and thenthermally at 100° C. for 18 hours. After cooling to room temperature,the crude residue was partitioned between water and EtOAc. The aqueousphase was further extracted with EtOAc (×2) and the combined organiclayers were washed with brine, dried (MgSO₄) and concentrated underreduced pressure. The resultant residue was purified by columnchromatography on silica gel eluting with 0-10% EtOAc in cyclohexane toafford the title compound as an off-white solid (0.352 g, 90% yield).LCMS (Method D): RT=4.68 min, m/z: 430 [M+H⁺].

Step 2.{6-[2-(4-tert-Butoxycarbonylamino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-carbamicacid tert-butyl ester (0.150 g, 0.35 mmol),(6-aminopyrimidin-4-yl)-bis-carbamic acid tert-butyl ester (0.118 g,0.38 mmol), XantPhos (0.020 g, 0.035 mmol) and Cs₂CO₃ (0.285 g, 0.875mmol) in dioxane (4 mL) was degassed with a stream of argon. Pd₂(dba)₃(0.016 g, 0.017 mmol) was then added and the reaction mixture was heatedat 80° C. for 2 hours in a sealed vial. After standing at roomtemperature for 18 hours, the resultant mixture was heated at 80° C. for5 hours. After cooling to room temperature, the crude reaction mixturewas partitioned between water and EtOAc. The aqueous phase was furtherextracted with EtOAc (×2) and the combined organic layers were washedwith brine, then dried (MgSO₄) and concentrated under reduced pressure.The resultant residue was purified by column chromatography on silicagel eluting with 0-20% EtOAc in cyclohexane to afford the title compoundas a yellow solid (86 mg, 35% yield). LCMS (Method D): RT=4.80 min, m/z:704 [M+H⁺].

Step 3.N-[2-(4-Amino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diaminehydrochloride salt

A solution of{6-[2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (86 mg, 0.122 mmol) in HCl (4N in dioxane, 3 mL)was heated at 50° C. for 3 hours, under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was filtered and thesolid collected and washed with dioxane followed by 1% MeOH/DCM toafford the title compound as an off-white solid (55 mg, 100% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 11.40 (br s, 1H), 8.21 (br s, 1H), 8.50 (s,1H), 8.44 (d, J=5.7 Hz, 1H), 7.88 (d, J=5.7 Hz, 1H), 6.78 (s, 2H), 6.28(br s, 2H). LCMS (Method C): RT=2.81 min, m/z: 404 [M+H⁺].

Example 132[2-(4-Amino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

Step 1.{3,5-Dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-carbamicacid tert-butyl ester

A mixture of[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-carbamicacid tert-butyl ester (0.30 g, 0.697 mmol), 6-methylpyrimidin-4-ylamine(0.073 g, 0.77 mmol), XantPhos (0.040 g, 0.0696 mmol) and Cs₂CO₃ (0.454g, 1.39 mmol) in dioxane (10 mL) was degassed with a stream of argon.Pd₂(dba)₃ (0.032 g, 0.035 mmol) was added and the reaction mixture washeated at 85° C. for 18 hours. After cooling to room temperature, thecrude reaction mixture was filtered through Celite® washing with EtOAcand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with0-30% EtOAc in petroleum ether to afford the title compound as a yellowsolid (0.238 g, 68% yield). LCMS (Method D): RT=3.14 min, m/z: 503[M+H⁺].

Step 2.[2-(4-Amino-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

A solution of{3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-carbamicacid tert-butyl ester (235 mg, 0.467 mmol) in 4N HCl in dioxane (10 mL)was heated at 50° C. for 3 hours under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was filtered and theprecipitate collected. The solid thus obtained was purified by columnchromatography on silica gel eluting with 0-5% 2N NH₃/MeOH in EtOAc toafford the title compound as a pale yellow solid (142 mg, 75% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 8.41(d, J=5.6 Hz, 1H), 7.77 (d, J=5.6 Hz, 1H), 7.63 (s, 1H), 6.77 (s, 2H),6.22 (s, 2H), 2.39 (s, 3H). LCMS (Method C): RT=2.97 min, m/z: 403[M+H⁺].

Example 133{4-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3,5-dichlorophenyl}-methanolformate salt

Step 1.{6-[2-(2,6-Dichloro-4-hydroxymethylphenyl)thiazolo[5,4-c]pyridine-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridine-2-yl)phenyl]-methanol(0.270 g, 0.78 mmol), (6-aminopyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (0.267 g, 0.86 mmol), XantPhos (0.045 g, 0.078 mmol)and Cs₂CO₃ (0.635 g, 1.954 mmol) in dioxane (6 mL) was degassed with astream of argon. Pd₂(dba)₃ (0.036 g, 0.039 mmol) was added and thereaction mixture was heated at 80° C. for 5 hours. After cooling to roomtemperature, the crude residue was left standing at room themperaturefor 18 hours and then was filtered through Celite® washing with EtOAc.The organic layer was washed with water and the aqueous phase wasfurther extracted with EtOAc (×2). The combined organic layers weredried (MgSO₄) and concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with0-30% EtOAc in cyclohexane to afford the title compound as a pale yellowsolid (0.150 g, 31% yield). LCMS (Method D): RT=3.99 min, m/z: 619[M+H⁺].

Step 2.{4-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3,5-dichloro-phenyl}methanolformate salt

A solution of{6-[2-(2,6-dichloro-4-hydroxymethylphenyl)thiazolo[5,4-c]pyridine-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (147 mg, 0.24 mmol) in HCl (1.25N in isopropanol,3 mL) was heated at 50° C. for 18 hours, under a nitrogen atmosphere.After cooling to room temperature, the reaction mixture was filtered andthe solid collected and washed with isopropanol. The solid was purifiedby reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 minutegradient 20-60%, 0.1% HCO₂H in MeOH/H₂O) to afford the title compound asa yellow solid/foam (45 mg, 41% yield). ¹H NMR (400 MHz, DMSO-d₆): δ10.08 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.73(d, J=5.6 Hz, 1H), 7.64 (s, 2H), 6.86 (s, 1H), 6.65 (s, 2H), 4.63 (s,2H). LCMS (Method C): RT=2.70 min, m/z: 419 [M+H⁺].

Example 134N-[2-(4-Aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diaminehydrochloride salt

Step 1.{6-[2-(2,6-Dichloro-4-cyanophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of4-(4-aminothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.370g, 1.15 mmol), (6-chloropyrimidin-4-yl)-bis-carbamic acid tert-butylester (0.437 g, 1.32 mmol), XantPhos (0.067 g, 0.115 mmol) and Cs₂CO₃(0.938 g, 2.88 mmol) in dioxane (6 mL) was degassed with a stream ofargon. Pd₂(dba)₃ (0.053 g, 0.058 mmol) was added and the reactionmixture was heated at 80° C. for 1 hour. After cooling to roomtemperature, the crude residue was filtered through Celite® washing withdiethyl ether. A precipitate formed in the filtrate and was collected byfiltration (42 mg). The organic layer was washed with water and theaqueous phase was further extracted with diethyl ether (×3). Thecombined organic layers were dried (MgSO₄) and concentrated underreduced pressure. The resultant residue was combined with the solidobtained by filtration (42 mg) and purified by column chromatography onsilica gel eluting with 0-40% diethyl ether in petroleum ether to affordthe title compound as a yellow solid/foam (0.293 g, 42% yield). LCMS(Method D): RT=4.46 min, m/z: 614 [M+H⁺].

Step 2.{6-[2-(4-Aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

To a solution of{6-[2-(2,6-dichloro-4-cyanophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (0.10 g, 0.163 mmol) in MeOH (1 mL) at 0° C., andunder a nitrogen atmosphere, were added 2N NH₃ in MeOH (0.407 mL, 0.815mmol) and CoCl₂.6H₂O (39 mg, 0.163 mmol) followed by sodium borohydride(31 mg, 0.815 mmol). The reaction mixture was stirred at 0° C. for 15minutes and then was quenched by addition of HCl (1N, 2 mL). Thevolatiles were removed under reduced pressure and the resultant residuewas loaded onto an Isolute® SCX-2 cartridge. The cartridge was washedwith MeOH and the product eluted with 0.2N NH₃ in MeOH. The basicfractions were combined and concentrated under reduced pressure toafford the title compound (60 mg) which was combined with the crudematerial obtained following the same method using{6-[2-(2,6-dichloro-4-cyanophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (0.164 g, 0.270 mmol). The resultant residue waspurified by column chromatography on silica gel eluting with 2% NH₃/MeOHin EtOAc to afford the title compound (48 mg, 18% yield). LCMS (MethodD): RT=2.71 min, m/z: 618 [M+H⁺].

Step 3.N-[2-(4-Aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diaminehydrochloride salt

A suspension of{6-[2-(4-aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (47 mg, 0.076 mmol) in HCl (4N in dioxane, 3 mL)was heated at 45° C. for 3 hours, under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was filtered and thesolid was collected and then washed with dioxane, then diethyl ether,DCM, EtOAc and finally with CH₃CN to afford the title compound as a paleyellow solid (31 mg, 90% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.63-8.40(m, 5H), 7.93-7.87 (m, 3H), 4.19 (q, J=5.4 Hz, 2H). LCMS (Method C):RT=1.93 min, m/z: 418 [M+H⁺].

Example 135[2-(4-Aminomethyl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-aminebis formate salt

NaBH₄ (0.137 g, 3.63 mmol) was added in one portion to a solution of3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]benzonitrile,0.50 g, 1.21 mmol), 2N NH₃ in MeOH (3.03 mL, 6.05 mmol) and COCl₂.6H₂O(0.288 g, 1.21 mmol) in a mixture of MeOH (10 mL) and THF (15 mL) at 0°C. under a nitrogen atmosphere. After stirring at 0° C. for 0.5 hour,the reaction mixture was quenched by addition of 1N HCl (15 mL) and thenconcentrated under reduced pressure. The resultant residue was loadedonto an Isolute® SCX-2 cartridge that was washed with MeOH and theproduct eluted with 0.2M NH₃ in MeOH. The relevant fractions werecombined and concentrated under reduced pressure. This crude product wascombined with the further product obtained by reacting3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile,0.050 g, 0.121 mmol) under the same reaction conditions. The resultantcombined crude residues were purified by silica gel flash chromatographyeluting with 0-2% 2M NH₃/MeOH in EtOAc, followed by reverse phase HPLC(Phenomenex Gemini 5 μm C18 on a gradient 10-40%, 0.1% HCO₂H inMeOH/H₂O) to give the title compound as a pale yellow solid (0.072 g,13% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.63 (d, J=1.2 Hz, 1H), 8.45(d, J=5.6 Hz, 1H), 8.24 (s, 2H), 7.83 (d, J=5.6 Hz, 1H), 7.74 (s, 2H),7.60 (s, 1H), 3.93 (s, 2H), 2.40 (s, 3H). LCMS (Method C): RT=2.10 min,m/z: 417 [M+H⁺].

Example 136[2-(2,6-Dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

Step 1. 4-Chloro-2-(2,6-dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridine

A mixture of4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.300 g,0.68 mmol), racemic-2-di-t-butylphosphino-1,1′-binaphthyl (0.035 g,0.0884 mmol), Pd(OAc)₂ (0.015 g, 0.068 mmol), Cs₂CO₃ (0.332 g, 1.02mmol) and MeOH (0.275 mL, 6.8 mmol) in toluene (3 mL) was degassed witha stream of argon and the reaction mixture was heated at 70° C. for 18hours. After cooling to room temperature, additionalracemic-2-di-t-butylphosphino-1,1′-binaphthyl (0.035 g) and Pd(OAc)₂(0.015 g) were added. The resulting mixture was then degassed with astream of argon and heated at 70° C. for 18 hours. The crude reactionmixture was filtered through Celite® and the filtrate was combined withtwo crude reaction mixtures obtained following the same method using4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.46mmol). The volatiles were removed under reduced pressure and theresultant residue was purified by column chromatography on silica geleluting with 0-10% diethyl ether in petroleum ether to afford the titlecompound as an off-white solid (116 mg, 30% yield). LCMS (Method D):RT=4.34 min, m/z: 345 [M+H⁺].

Step 2.[2-(2,6-Dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

A mixture of4-chloro-2-(2,6-dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridine (0.113g, 0.328 mmol), 6-methylpyrimidin-4-ylamine (0.031 g, 0.328 mmol),XantPhos (0.019 g, 0.033 mmol), Pd₂(dba)₃ (0.015 g, 0.0164 mmol) andCs₂CO₃ (0.213 g, 0.655 mmol) in dioxane (3 mL) was degassed with astream of argon and the reaction mixture was heated at 85° C. for 18hours. After cooling to room temperature and standing at roomtemperature for 56 hours, additional XantPhos (0.019 g) and Pd₂(dba)₃(0.015 g) were added. The resultant mixture was then degassed with astream of argon and heated at 110° C. for 1 hour using microwaveirradiation. Additional XantPhos (0.010 g), Pd₂(dba)₃ (0.008 g) and6-methylpyrimidin-4-ylamine (0.006 g) were added and the resultingsuspension was then degassed with a stream of argon and heated at 110°C. for 1 hour using microwave irradiation. The crude reaction mixturewas filtered through Celite® and the filtrate was concentrated underreduced pressure. The resultant residue was purified by columnchromatography on silica gel eluting with 0-2% MeOH in DCM followed byreverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 30 minute gradient10-80%, 0.1% HCO₂H in CH₃CN/H₂O) to afford the title compound as anoff-white solid (36 mg, 26% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.91(s, 1H), 8.54 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.73 (s, 1H),7.36 (s, 2H), 3.92 (s, 3H), 2.49 (s, 3H). LCMS (Method D): RT=3.65 min,m/z: 418 [M+H⁺].

Example 137[2-(4-Azetidin-3-yl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

Step 1.3-[3,5-Dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-azetidine-1-carboxylicacid tert-butyl ester

Zinc dust (0.116 g, 1.77 mmol) and celpure P65 (0.025 g) were stirredunder an argon atmosphere for 30 minutes. N,N-dimethylacetamide (0.5 mL)was added followed by 1,2-dibromoethane (0.014 mL, 0.163 mmol) andtrimethylsilyl chloride (0.021 mL, 0.163 mmol). The reaction mixture wasstirred at room temperature for 15 minutes, then a solution of3-iodoazetidine-1-carboxylic acid tert-butyl ester (0.385 g, 1.36 mmol)in N,N-dimethylacetamide (1 mL) was added and stirring at roomtemperature was continued for 1.5 hours. The resultant mixture wasfiltered and the filtrate was added to a suspension of4-chloro-2-(2,6-dichloro-4-iodophenyl)-thiazolo[5,4-c]pyridine (0.30 g,0.68 mmol), PdCl₂(dppf).DCM (0.052 g, 0.068 mmol) and CuI (0.016 g,0.088 mmol) in N,N-dimethylacetamide (4 mL) previously degassed with astream of argon. The reaction mixture was heated at 80° C. for 2 hoursand then allowed to cool to room temperature. The crude mixture waspartitioned between diethyl ether and water and the aqueous phase wasextracted with diethyl ether (×2). The combined organic layers werewashed with brine, dried (MgSO₄) and concentrated under reducedpressure. The resultant residue was purified by column chromatography onsilica gel eluting with 0-70% Et₂O in petroleum ether to afford thetitle compound as an off-white solid (108 mg, 34%). LCMS (Method D):RT=4.66 min, m/z: 470 [M+H⁺].

Step 2.3-{3,5-Dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-azetidine-1-carboxylicacid tert-butyl ester

A mixture of3-[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-azetidine-1-carboxylicacid tert-butyl ester (0.106 g, 0.225 mmol), 6-methylpyrimidin-4-ylamine(0.024 g, 0.248 mmol), XantPhos (0.013 g, 0.023 mmol), Pd₂(dba)₃ (0.010g, 0.0113 mmol) and Cs₂CO₃ (0.147 g, 0.45 mmol) in dioxane (2 mL) wasdegassed with a stream of argon. The reaction mixture was heated at 85°C. for 18 hours. Additional Pd₂(dba)₃ (0.005 g), XantPhos (0.007 g) and6-methylpyrimidin-4-ylamine (0.006 g) were added and the mixture washeated at 85° C. for 18 hours. After cooling to room temperature, thecrude reaction mixture was filtered through Celite® and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel eluting with 0-90% EtOAc inpetroleum ether to afford the title compound as a pale yellow glass (64mg, 52% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.71 (s, 1H), 8.45 (d, J=5.7Hz, 1H), 8.15 (s, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.51-7.41 (m, 3H), 4.39(t, J=8.7 Hz, 2H), 4.02-3.92 (m, 2H), 3.80-3.70 (m, 1H), 2.56 (s, 3H),1.48 (s, 9H).

Step 3.[2-(4-Azetidin-3-yl-2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

HCl (4N in dioxane, 5 mL) was added to3-{3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-azetidine-1-carboxylicacid tert-butyl ester (0.062 g, 0.114 mmol). The suspension was heatedat 40° C. for 1 hour and then cooled to room temperature. The volatileswere removed under reduced pressure and the resultant residue wastriturated with a mixture of EtOAc/DCM and then purified by columnchromatography on silica gel eluting with 0-5% 2N NH₃/MeOH in DCM toafford the title compound as an off-white solid (20 mg, 40% yield). ¹HNMR (400 MHz, CDCl₃): δ 8.65 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H),7.84 (d, J=5.6 Hz, 1H), 7.75 (s, 2H), 7.63 (s, 1H), 3.99-3.90 (m, 1H),3.85 (t, J=7.6 Hz, 2H), 3.61 (t, J=6.9 Hz, 2H), 2.41 (s, 3H). LCMS(Method C): RT=2.21 min, m/z: 443 [M+H⁺].

Example 138[2-(2,6-Dichloro-4-cyclopropylphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

Step 1.4-Chloro-2-(2,6-dichloro-4-cyclopropylphenyl)thiazolo[5,4-c]pyridine

A mixture of4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.20 g,0.45 mmol), cyclopropyl boronic acid (0.051 g, 0.59 mmol), Pd(OAc)₂(0.005 g, 0.023 mmol), P(Cy)₃ (tricyclohexylphosphine) (0.013 g, 0.045mmol) and potassium phosphate tribasic (0.336 g, 1.58 mmol) in toluene(4 mL) and water (0.2 mL) was degassed with a stream of argon and thenheated at 100° C. for 18 hours. After cooling to room temperature, thecrude reaction mixture was filtered through Celite® washing with EtOAc.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with brine, then dried (MgSO₄) and concentrated underreduced pressure. The resultant residue was combined with the crudereaction mixture (79 mg) obtained by reacting4-chloro-2-(2,6-dichloro-4-iodophenyl)-thiazolo[5,4-c]pyridine (0.10 g,0.23 mmol) under the same reaction conditions and purified by columnchromatography on silica gel eluting with 0-30% Et₂O in petroleum ether(40-60° C.) to afford the title compound as a yellow/orange solid (148mg, 61%). LCMS (Method D): RT=4.69 min, m/z: 355 [M+H⁺].

Step 2.[2-(2,6-Dichloro-4-cyclopropylphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

A mixture of4-chloro-2-(2,6-dichloro-4-cyclopropylphenyl)thiazolo[5,4-c]pyridine(0.148 g, 0.416 mmol), 6-methylpyrimidin-4-ylamine (0.044 g, 0.458mmol), XantPhos (0.024 g, 0.0416 mmol), Cs₂CO₃ (0.271 g, 0.832 mmol) andPd₂(dba)₃ (0.019 g, 0.021 mmol) in dioxane (1 mL) was degassed with astream of argon and was then irradiated at 150° C. for 0.5 hour in amicrowave reactor. After cooling to room temperature, the crude reactionmixture was filtered through Celite® washing with DCM and the filtratewas concentrated under reduced pressure. The resultant residue waspurified by column chromatography on silica gel eluting with 0-2% MeOHin DCM followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a30 minute gradient 50-90%, 0.1% HCO₂H in MeOH/H₂O) to afford the titlecompound (7 mg, 4% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H),8.63 (d, J=1.2 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.82 (d, J=5.6 Hz, 1H),7.62 (s, 1H), 7.45 (s, 2H), 2.40 (s, 3H), 2.14-2.05 (m, 1H), 1.13-1.07(m, 2H), 0.94-0.89 (m, 2H). LCMS (Method C): RT=4.17 min, m/z: 428[M+H⁺].

Example 139N-(3,5-dichloro-4-(4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl)phenyl)acetamide

Step 1.1-[3,5-Dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)phenyl]-acetamide

A mixture of4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.150 g,0.34 mmol), acetamide (0.024 g, 0.41 mmol), copper(I) iodide (0.010 g,0.05 mmol), dimethylamino-acetic acid (0.007 g, 0.068 mmol) andpotassium phosphate (0.360 g, 1.70 mmol) in DMSO (1 mL) was degassedwith a stream of nitrogen and then heated at 80° C. for 16 hours. Aftercooling to room temperature, the crude reaction mixture was partitionedbetween EtOAc and water. The organic layer was washed with brine, thendried (Na₂SO₄) and concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with50% EtOAc in cyclohexane to afford the title compound as a pale yellowsolid (52 mg, 45% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.52 (d, J=5.6 Hz,1H), 8.06 (s, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.72 (s, 2H), 2.23 (s, 3H).

Step 2.N-{3,5-Dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-acetamide

A mixture ofN-[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-acetamide(0.057 g, 0.15 mmol), 6-methylpyrimidin-4-ylamine (0.020 g, 0.18 mmol),Pd₂(dba)₃ (0.007 g, 0.0075 mmol), XantPhos (0.017 g, 0.03 mmol) andCs₂CO₃ (0.098 g, 0.30 mmol) in dioxane (2 mL) was degassed with a streamof N₂ and then subjected to microwave irradiation at 150° C. for 30minutes. After cooling to room temperature, the crude reaction mixturewas partitioned between EtOAc and water. The organic layer was washedwith brine, then dried (Na₂SO₄) and concentrated under reduced pressure.The resultant residue was purified by column chromatography on silicagel eluting with 50-100% EtOAc in cyclohexane followed by 1% MeOH inEtOAc to afford the title compound as a pale yellow solid (21 mg, 31%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 1H), 10.53 (s, 1H), 8.63(d, J=1.2 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.89 (s, 2H), 7.82 (d, J=5.6Hz, 1H), 7.61 (s, 1H), 2.39 (s, 3H), 2.13 (s, 3H). LCMS (Method C):RT=3.02 min, m/z: 445 [M+H⁺].

Example 140[2-(2-Chloro-6-fluorophenyl)-7-fluorthiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

Step 1. 2-Chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide

2-Chloro-6-fluorobenzoyl chloride (13.6 g, 71.6 mmol) was addeddropwise, over 10 minutes, to a solution of3,5-difluoro-pyridin-4-ylamine (7.7 g, 59.3 mmol) in pyridine (100 mL)at 0° C. under argon and the reaction mixture was stirred at 0° C. for 3hours. The volatiles were removed under reduced pressure and theresultant residue was treated with 1N HCl (100 mL). The resultantsuspension was stirred at room temperature for 2 hours and then thesolid was collected by filtration, washing with water. A mixture of2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide, LCMS (MethodE): RT=2.83 min, m/z: 287 [M+H⁺], and of2-chloro-N-(2-chloro-6-fluorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamideLCMS (Method E): RT=3.96 min, m/z: 443 [M+H⁺], (23 g) was obtained whichwas used in the following step without further purification.

A suspension of the crude mixture (23 g) and 1M NaOH (200 mL) in MeOH(200 mL) was stirred at room temperature for 2 hours. Additional amountsof 1M NaOH (200 mL) and of MeOH (200 mL) were added and stirring at roomtemperature was continued for 2 hours and then at 80° C. for 1 hour.After cooling to room temperature, the mixture was made acidic byaddition of conc HCl (33 mL). The suspension was evaporated in vacuo tohalf of the original volume and the residue was collected by filtration,washed with water and dried to afford the title compound as a creamsolid (11.6 g, 68%). LCMS (Method E): RT=2.76 min, m/z: 287 [M+H⁺].

Step 2. 2-Chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzimidoylchloride

A stirred suspension of2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide (11.4 g, 0.04mol) in thionyl chloride (100 mL) was heated at 100° C. for 18 hours.After cooling to room temperature, the volatiles were removed underreduced pressure. The resulting residue was azeotroped with toluene (100mL). The crude residue was triturated with diethyl ether to afford thetitle compound as an off-white solid (12.1 g, quantitative). LCMS(Method E): RT=3.88 min, m/z: 305 [M+H⁺].

Step 3. 2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine

A stirred suspension of2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzimidoyl chloride (12.0g, 39.4 mmol), thiourea (9.0 g, 118 mmol) and pyridine (12.7 mL, 198mmol) in isopropanol (200 mL) was heated at 150° C. for 3.5 hours. Afterstirring for one additional hour, the resulting precipitate wascollected by filtration. The filtrate was treated with Et₃N (27 mL,0.197 mol) and heating was continued at 150° C. for 18 hours. Aftercooling to room temperature, the volatiles were removed under reducedpressure and the resultant residue was partitioned between EtOAc (300mL) and water (500 mL). The aqueous phase was extracted with EtOAc(2×300 mL) and the combined organic layers were dried and concentratedunder reduced pressure. The resultant residue was purified by columnchromatography on silica gel eluting with 0-100% Et₂O in petroleum etherand then triturated with a mixture 3:1 diethyl ether:pentane (25 mL) toafford the title compound as a cream coloured solid (4.6 g, 41%). LCMS(Method F): RT=3.39 min, m/z: 283 [M+H⁺].

Step 4. 2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine5-oxide

To an ice-cooled solution of2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.0 g,14.16 mmol) in DCM (50 mL) was added m-CPBA (4.82 g, 0.028 mol) and themixture was stirred at 5° C. for 1 hour. Additional m-CPBA (4.82 g, 28.0mmol) was added and stirring at room temperature was continued for 18hours. The suspension was diluted with DCM (50 mL) and washed with apotassium carbonate solution (100 mL). The aqueous phase was extractedwith DCM (2×50 mL) and the combined organic layers were washed withwater (100 mL), then dried (Na₂SO₄) and concentrated under reducedpressure. The resultant residue was triturated with diethyl ether (25mL) to afford the title compound as a white solid (3.1 g, 73%). LCMS(Method E): RT=2.70 min, m/z: 299 [M+H⁺].

Step 5. 4-Chloro-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine

A stirred solution of2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (3.0g, 10.5 mmol) in phosphoryl chloride (50 mL) was heated at 110° C. for45 minutes. After cooling to room tempetarure, the volatiles wereremoved under reduced pressure and the resultant residue was partitionedbetween a potassium carbonate saturated solution (100 mL) and EtOAc (50mL). The aqueous phase was extracted with EtOAc (2×50 mL) and thecombined organic layers were washed with water (100 mL), dried andconcentrated under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel eluting with 10% diethyl ether inpentane to afford the title compound as a colourless solid (0.71 g, 22%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.38 (s, 1H), 7.56-7.46 (m, 1H), 7.41(d, J=8.2 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H).

Step 6.4-Bromo-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine

Trimethylsilyl bromide (0.4 mL, 3 mmol) was added to a solution of4-chloro-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine(0.317 g, 1.0 mmol) in propionitrile (10 mL) at room temperature underan argon atmosphere. The reaction mixture was heated at 85° C. in asealed vial for three days then it was poured in an ice-cooled saturatedsolution of potassium carbonate. The resultant mixture was extractedwith DCM (×2). The combined organic washings were dried (Na₂SO₄) andconcentrated under reduced pressure to afford the title compound as anoff-white solid (0.365 g, quantitative). ¹H NMR (400 MHz, CDCl₃): δ 8.39(d, J=1.9 Hz, 1H), 7.51 (td, J=8.3, 5.8 Hz, 1H), 7.41 (dt, J=8.2, 1.1Hz, 1H), 7.25-7.16 (m, 1H).

Step 7.[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

A mixture of4-bromo-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine(0.09 g, 0.25 mmol), 6-methylpyrimidin-4-ylamine (0.027 g, 0.25 mmol),XantPhos (0.015 g, 0.025 mmol) and Cs₂CO₃ (0.206 g, 0.625 mmol) indioxane (2 mL) was degassed with a stream of argon. Pd₂(dba)₃ (0.012 g,0.0125 mmol) was added and the reaction mixture was heated in a sealedvial at 70° C. for 5 hours. After allowing to cool to room temperature,a stream of argon was bubbled through the suspension and additionalamounts of Pd₂(dba)₃ (0.010 g) and XantPhos (0.010 g) were added. Thereaction mixture was heated at 80° C. for 18 hours. After cooling toroom temperature, the crude mixture was filtered through Celite® washingwith EtOAc and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 0-100% EtOAc in pentane and then triturated with diethylether to afford the title compound as an off-white solid (41 mg, 42%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.71 (s, 1H), 8.30 (d, J=1.9 Hz, 1H),7.87 (s, 1H), 7.57-7.45 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.21 (t, J=8.7Hz, 1H), 2.55 (s, 3H). LCMS (Method C): RT=3.54 min, m/z: 390 [M+H⁺].

Example 141N-[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diaminehydrochloride salt

Step 1.[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester

A mixture of4-bromo-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine(0.440 g, 1.22 mmol), carbamic acid tert-butyl ester (0.714 g, 6.1mmol), XantPhos (0.071 g, 0.122 mmol) and K₃PO₄ (0.530 g, 2.5 mmol) intoluene (8 mL) and water (1.2 mL) was degassed with a stream of argon.Pd₂(dba)₃ (0.056 g, 0.061 mmol) was added and the reaction mixture washeated in a sealed vial at 70° C. for 3 hours. After cooling to roomtemperature, the crude mixture was filtered through Celite® washing withEtOAc. The organic layer was washed with brine, then dried (Na₂SO₄) andconcentrated under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel eluting with 0-50% EtOAc inpentane to afford the title compound as a white solid (350 mg, 72%yield). LCMS (Method D): RT=4.08 min, m/z: 398 [M+H⁺].

Step 2.2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine

HCl (4N in dioxane, 10 mL) was added to[2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester (0.350 g, 0.88 mmol) and the reaction mixture washeated at 50° C. for 3 hours. After cooling to room temperature, thevolatiles were removed under reduced pressure to afford the titlecompound as an off-white solid (270 mg, quantitative). ¹H NMR (400 MHz,CDCl₃): δ 7.84 (s, 1H), 7.61-7.49 (m, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.25(t, J=8.7 Hz, 1H), 2.90 (br s, 2H).

Step 3.{6-[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine(0.130 g, 0.440 mmol), (6-chloropyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (0.189 g, 0.57 mmol), XantPhos (0.025 g, 0.049 mmol)and Cs₂CO₃ (0.360 g, 1.10 mmol) in dioxane (4.5 mL) was degassed with astream of argon. Pd₂(dba)₃ (0.070 g, 0.022 mmol) was added and thereaction mixture was heated at 70° C. for 7 hours. The resultant mixturewas diluted with DMF (1.5 mL) and degassed with a stream of argon priorto addition of Pd₂(dba)₃ (0.020 g) and XantPhos (0.025 g). Thesuspension was heated at 80° C. for 18 hours and then cooled to roomtemperature. The crude reaction mixture was filtered through Celite®washing with EtOAc (50 mL) and the filtrate was washed with brine, thendried (Na₂SO₄) and concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with0-50% EtOAc in pentane followed by 0-20% EtOAc in DCM to afford thetitle compound as a yellow glass (186 mg). LCMS (Method D): RT=4.60 min,m/z: 591 [M+H⁺].

Step 4.N-[2-(2-Chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diaminehydrochloride salt

To a mixture of{6-[2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (0.186 g) in DCM (5 mL) was added TFA (0.5 mL) atroom temperature under argon. The reaction mixture was stirred at roomtemperature for 18 hours. The volatiles were removed under reducedpressure and the resultant residue was dissolved in DCM and washed witha saturated solution of NaHCO₃, by brine and then dried (Na₂SO₄) andconcentrated under reduced pressure. The resultant residue was purifiedby reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 35 minutegradient 20-80%, 0.1% NH₄OH in CH₃CN/H₂O) to affordN-[2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-pyrimidine-4,6-diamineas an off-white solid (58 mg). The product thus obtained was stirred inHCl (1.25N in isopropanol) at room temperature for 18 hours. Thevolatiles were removed under reduced pressure to afford the titlecompound as a white solid (64 mg, 34% over three steps). ¹H NMR (400MHz, DMSO-d₆): δ 11.69 (br s, 1H), 8.51 (d, J=11.5 Hz, 1H), 8.32 (br s,1H), 7.80-7.71 (m, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.55 (t, J=8.9 Hz, 1H),7.05 (br s, 1H). LCMS (Method C): RT=3.18 min, m/z: 391 [M+H⁺].

Example 142[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

Step 1. 2,6-Dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide

2,6-Dichlorobenzoyl chloride (13.7 mL, 95.6 mmol) was added dropwise,over 10 minutes, to a solution of 3,5-difluoropyridin-4-ylamine (10.37g, 79.7 mmol) in pyridine (160 mL) at a temperature of between 3 and 5°C., under argon. The reaction mixture was allowed to warm to roomtemperature over 1 hour and then stirred at room temperature for 2hours. The volatiles were removed under reduced pressure and theresultant residue was treated with HCl (1N, 120 mL). The resultantsuspension was stirred at room temperature for 45 minutes and theprecipitate was collected by filtration, washing with water. A mixtureof 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide and of2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-benzamide(22.0 g) was obtained.

A suspension of this mixture (22.0 g) in 1N NaOH (200 mL) and MeOH (200mL) was heated at 65° C. for 7 hours then slowly cooled to roomtemperature. The pH of the mixture was adjusted to 4-5 by dropwiseaddition of 12N HCl, controlling the exotherm by the use of an ice-bath.The residue was left standing at room temperature for 18 hours and thenthe resultant solid was collected by filtration, washing with water, toafford the title compound as an off-white solid (14.65 g, 61% yield overtwo steps). LCMS (Method D): RT=2.93 min, m/z: 303 [M+H⁺].

Step 2. 2,6-Dichloro-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride

A stirred suspension of2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide (14.5 g, 47.8 mmol)in thionyl chloride (130 mL) was heated at 85° C. for 20 hours and thenat 90° C. for 26 hours under argon. After cooling to room temperature,the volatiles were removed under reduced pressure, azeotroped withtoluene (×3) to afford the title compound as a yellow solid (15.7 g,quantitative). LCMS (Method D): RT=4.16 min, m/z: 321 [M+H⁺].

Step 3. 2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine

A stirred suspension of2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride (15.4 g,47.8 mmol), thiourea (14.5 g, 0.191 mol) and pyridine (19.3 mL, 0.239mol) in isopropanol (250 mL) was heated at 85° C. for 4 hours underargon. To the mixture was added Et₃N (40 mL, 0.287 mol) and heating at85° C. was continued for 18 hours. After cooling to room temperature,the volatiles were removed under reduced pressure and the resultantresidue was partitioned between EtOAc (500 mL) and water (500 mL). Theaqueous phase was extracted with EtOAc (300 mL) and the combined organiclayers were washed with water, then dried (Na₂SO₄) and concentratedunder reduced pressure. The resultant residue was purified by columnchromatography on silica gel eluting with 0-50% EtOAc in pentane toafford the title compound as a pale yellow solid (8.5 g, 59%). LCMS(Method D): RT=3.56 min, m/z: 299 [M+H⁺].

Step 4. 2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide

To an ice-cooled solution of2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (5.1 g, 17.1mmol) in DCM (70 mL), was added m-CPBA (11.77 g, 68.2 mmol) over 3minutes, at 0° C. under argon. The reaction mixture was slowly warmed toroom temperature over 1 hour and then stirred at room temperature for 4hours. The resultant mixture was diluted with DCM (150 mL) and washedwith a saturated solution of potassium carbonate (100 mL). Additionalamounts of DCM and water were added, followed by MeOH (50 mL). Theorganic layer was separated, washed with water (300 mL), dried (Na₂SO₄)and concentrated under reduced pressure. The resultant residue wastriturated with water, dried under reduced pressure to afford the titlecompound as a white solid (6.50 g, quantitative). LCMS (Method F):RT=2.76 min, m/z: 315 [M+H⁺].

Step 5. 4-Chloro-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine

A stirred solution of2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (0.095 g,0.30 mmol) in phosphoryl chloride (3 mL) was heated under reflux for 0.5hour and then at 110° C. for 15 minutes. The reaction was repeated on alarger scale by reacting2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (6.4 g,17.0 mmol) with phosphoryl chloride (100 mL) and by heating the mixtureunder reflux for 30 minutes. After cooling to room temperature, themixture was left standing at room temperature for 18 hours and thenheated at reflux temperature for 15 minutes. The two crude reactionmixtures were combined and the volatiles were removed under reducedpressure. The crude residue was dissolved in EtOAc (200 mL) and washedwith a saturated solution of potassium carbonate, followed by water,then dried (Na₂SO₄) and concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 0-20% EtOAc in pentane to afford the title compound as awhite solid (3.42 g, 49% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.39 (d,J=1.9 Hz, 1H), 7.53-7.41 (m, 3H).

Step 6. 4-Bromo-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine

Trimethylsilyl bromide (1.2 mL, 9.0 mmol) was added to a solution of4-chloro-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (1.0 g,3.0 mmol) in propionitrile (30 mL) at room temperature under argon. Thereaction mixture was heated at 85° C. in a sealed vial for 16 hours. Theresultant mixture was poured in an ice-cooled saturated solution ofpotassium carbonate. The product was extracted with DCM (×2) and thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to afford the title compound as an off-white solid(1.17 g, quantitative). LCMS (Method E): RT=4.32 min, m/z: 379 [M+H⁺].

Step 7.[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

A mixture of4-bromo-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.113 g,0.30 mmol), 6-methylpyrimidin-4-ylamine (0.036 g, 0.33 mmol), XantPhos(0.018 g, 0.030 mmol) and Cs₂CO₃ (0.247 g, 0.75 mmol) in dioxane (2.5mL) was degassed with a stream of argon. Pd₂(dba)₃ (0.014 g, 0.015 mmol)was added and the reaction mixture was heated in a sealed vial at 80° C.for 3 hours. After cooling to room temperature, the crude reactionmixture was filtered through Celite® washing with EtOAc and the filtratewas concentrated under reduced pressure. The resultant residue waspurified by column chromatography on silica gel eluting with 0-100%EtOAc in pentane and then triturated with diethyl ether to afford thetitle compound as an off-white solid (71 mg, 58% yield). ¹H NMR (400MHz, DMSO-d₆): δ 10.68 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.49 (d, J=1.9Hz, 1H), 7.77-7.72 (m, 2H), 7.71-7.66 (m, 1H), 7.42 (s, 1H), 2.38 (s,3H). LCMS (Method C): RT=3.73 min, m/z: 406 [M+H⁺].

Example 143[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamicacid methyl ester

Step 1.2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester

A mixture of4-bromo-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.60 g,1.6 mmol), carbamic acid tert-butyl ester (0.936 g, 8.0 mmol), XantPhos(0.093 g, 0.16 mmol) and K₃PO₄ (0.678 g, 3.2 mmol), in toluene (10 mL)and water (2 mL), was degassed with a stream of argon. Pd₂(dba)₃ (0.073g, 0.08 mmol) was added and the reaction mixture was heated at 70° C.for 3 hours in a sealed vial. After cooling to room temperature, thecrude reaction mixture was filtered through Celite® washing with EtOAc.The aqueous phase was further extracted with EtOAc and the combinedorganic layers were washed with brine, then dried (Na₂SO₄) andconcentrated under reduced pressure. The resultant residue was purifiedby column chromatography on silica gel eluting with 0-40% EtOAc inpentane to afford the title compound as an off-white/yellow solid (0.74g). LCMS (Method D): RT=4.26 min, m/z: 414 [M+H⁺].

Step 2. 2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine

To a solution of2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamicacid tert-butyl ester (0.70 g) in DCM (12 mL) under an argon atmosphereat room temperature was added TFA (3.0 mL). The reaction mixture wasstirred for 1 hour and 15 minutes. The volatiles were removed underreduced pressure and the resultant residue was loaded onto an Isolute®SCX-2 cartridge. The cartridge was washed with DCM:MeOH (1:1) and thenwith MeOH and the product eluted with 2N NH₃ in MeOH. The basicfractions were combined and concentrated under reduced pressure toafford the title compound as a white solid (305 mg, 60% over two steps).LCMS (Method F): RT=2.87 min, m/z: 314 [M+H⁺].

Step 3.[2-(2,6-Dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamicacid methyl ester

To a solution of methyl chloroformate (18 mg, 0.191 mmol) and DIPEA (42μL, 0.24 mmol) in THF (1.0 mL) was added2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine (50 mg,0.159 mmol). The reaction mixture was stirred at room temperature for2.5 hours, then heated at 50° C. for 2 hours and left standing at roomtemperature for 18 hours. The crude reaction mixture was partitionedbetween EtOAc and brine. The aqueous phase was extracted with EtOAc andthe combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. The resultant residue was purified by columnchromatography on silica gel eluting with 0-50% EtOAc in pentane toafford the title compound as a white solid (12 mg, 20%). ¹H NMR (400MHz, DMSO-d₆): δ 10.87 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.77-7.65 (m,3H), 3.73 (s, 3H). LCMS (Method C): RT=4.74 min, m/z: 372 [M+H⁺].

Example 1443,5-Dichloro-4-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrileformate salt

Step 1. 2,6-Dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzamide

NaH (461 mg, 11.54 mmol) was added portionwise to a solution of3,5-difluoropyridin-4-ylamine (1.0 g, 7.69 mmol) in DMF (20 mL) at 0° C.under a nitrogen atmosphere. A solution of 2,6-dichloro-4-cyano-benzoylchloride (1.98 g, 8.46 mmol) in DMF (15 mL) was then added whilstmaintaining the internal temperature below 10° C. Stirring was continuedfor 1.5 hours. The reaction mixture was quenched by addition of asaturated solution of NH₄Cl and partitioned between water and EtOAc. Theaqueous phase was further extracted with EtOAc (×2) and the combinedorganic layers were washed with water, then with brine, dried (MgSO₄)and concentrated under reduced pressure. The resultant residue wascombined with the crude reaction mixture obtained following the samemethod starting from 3,5-difluoro-pyridin-4-ylamine (100 mg, 0.77 mmol)and purified by column chromatography on silica gel eluting with 0-50%EtOAc in cyclohexane to afford the title compound as an off-white solid(1.35 g, 49% yield). LCMS (Method D): RT=3.02 min, m/z: 328 [M+H⁺].

Step 2. 2,6-Dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzimidoylchloride

A stirred suspension of2,6-dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzamide (1.35 g,4.12 mmol) in thionyl chloride (14 mL) was heated at 85° C. for 5 hoursand then at 80° C. for 56 hours under a nitrogen atmosphere. Aftercooling to room temperature, the volatiles were removed under reducedpressure to afford the title compound as an orange solid (1.5 g,quantitative). LCMS (Method D): RT=4.01 min, m/z: 346 [M+H⁺].

Step 3.3,5-Dichloro-4-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile

A stirred suspension of2,6-dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride(1.5 g, 4.33 mmol), thiourea (1.32 g, 17.34 mmol) and pyridine (1.19 mL,14.72 mmol) in isopropanol (13 mL) under a nitrogen atmosphere washeated at 90° C. for 4 hours. After cooling to 60° C., Et₃N (3.62 mL,25.98 mmol) was added and heating at 85° C. was continued for 18 hours,then at 90° C. for a further 18 hours. After cooling to roomtemperature, the volatiles were removed under reduced pressure and theresultant residue was partitioned between EtOAc and water. The aqueousphase was extracted with EtOAc (×2) and the combined organic layers weredried (MgSO₄) and concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with0-90% EtOAc in cyclohexane to afford the title compound as a yellowsolid (417 mg, 30%). LCMS (Method D): RT=3.53 min, m/z: 324 [M+H⁺].

Step 4.3,5-Dichloro-4-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile

To a solution of3,5-dichloro-4-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (413mg, 1.27 mmol) in DCM (5 mL) under a nitrogen atmosphere was addedmethyltrioxorhenium(VII) (32 mg, 0.127 mmol) followed by 30% aq.hydrogen peroxide (0.26 mL, 2.54 mmol). The reaction mixture was stirredat room temperature for 18 hours and then was quenched by addition of asaturated solution of NaHCO₃. The aqueous layer was extracted with DCM(×2). The combined organic phases were washed with brine, dried (MgSO₄)and concentrated under reduced pressure to afford the title compound asa yellow solid (259 mg, 60% yield). LCMS (Method D): RT=2.78 min, m/z:340 [M+H⁺].

Step 5.3,5-Dichloro-4-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile

A stirred solution of3,5-dichloro-4-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile(0.259 g, 0.76 mmol) in phosphoryl chloride (2.6 mL) was heated at 110°C. for 1 hour under a nitrogen atmosphere. After cooling to roomtemperature, the volatiles were removed under reduced pressure and theresultant residue was partitioned between EtOAc and a saturated solutionof NaHCO₃. The aqueous phase was extracted with EtOAc (×2) and thecombined organic layers were dried (MgSO₄) and concentrated underreduced pressure. The resultant residue was combined with the crudemixture obtained following the same method and using3,5-dichloro-4-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile(0.154 g, 0.453 mmol). The crude material (215 mg) was purified bycolumn chromatography on silica gel eluting with 0-10% EtOAc inpetroleum ether to afford the title compound as a yellow solid (132 mg,30% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.42 (d, J=1.8 Hz, 1H), 7.79 (s,2H).

Step 6.4-(4-Bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile

Trimethylsilyl bromide (0.14 mL, 1.08 mmol) was added to a solution of3,5-dichloro-4-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile(0.130 g, 0.36 mmol) in propionitrile (3 mL) at room temperature under anitrogen atmosphere. The reaction mixture was heated at 85° C. for 18hours then allowed to stand at room temperature for 48 hours. Theresultant mixture was poured into an ice-cooled saturated solution ofNaHCO₃ and extracted with EtOAc (×2). The combined organic layers weredried (MgSO₄) and concentrated under reduced pressure to afford thetitle compound as an off-white solid (131 mg, 90% yield). ¹H NMR (400MHz, CDCl₃): δ 8.42 (d, J=1.8 Hz, 1H), 7.78 (s, 2H).

Step 7.3,5-Dichloro-4-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)-thiazolidin-4-ylamino)[5,4-c]pyridin-2-yl]-benzonitrileformate salt

A mixture of4-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile(0.128 g, 0.318 mmol), 6-methylpyrimidin-4-ylamine (0.033 g, 0.35 mmol),XantPhos (0.019 g, 0.032 mmol) and Cs₂CO₃ (0.207 g, 0.635 mmol) indioxane (4 mL) was degassed with a stream of argon. Pd₂(dba)₃ (0.015 g,0.016 mmol) was added and the reaction mixture was heated at 80° C. for18 hours. After cooling to room temperature, the crude reaction mixturewas partitioned between EtOAc and water. The aqueous phase was extractedwith EtOAc (×2) and the combined organic layers were washed with brine,dried (MgSO₄) and concentrated under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with0-5% MeOH in DCM and then by reverse phase HPLC (Phenomenex Gemini 5 μmC18 on a 30 minute gradient 40-90%, 0.1% HCO₂H in MeOH/H₂O) to affordthe title compound as an off-white solid (44 mg, 30% yield). ¹H NMR (400MHz, DMSO-d₆): δ 10.72 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.50 (d, J=1.8Hz, 1H), 8.40 (s, 2H), 8.31 (s, 1H), 7.39 (s, 1H), 2.38 (s, 3H). LCMS(Method C): RT=3.71 min, m/z: 431 [M+H⁺].

Example 1452-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile

Step 1. 2-Bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzamide

A mixture of 2-chloro-3-fluoro-4-iodopyridine (9.0 g, 35 mmol),2-bromo-6-chlorobenzamide (9.0 g, 38.3 mmol), XantPhos (0.81 g, 1.40mmol), Cs₂CO₃ (19.8 g, 60.7 mmol) and Pd₂(dba)₃ (0.90 g, 1.0 mmol) indioxane (200 mL) was degassed with a stream of argon and then was heatedunder reflux for 1.5 hours. After cooling to room temperature, the crudereaction mixture was poured into a rapidly stirred mixture of water(1200 mL) and EtOAc (300 mL) and filtered through Celite® washing withEtOAc. The filtrate was partitioned between water (1.2 L) and EtOAc (300mL) and the organic layer was washed with additional water (300 mL),then dried and concentrated to dryness under reduced pressure. Theresultant residue was heated in isopropanol (100 mL) under reflux for 30minutes and the suspension was allowed to cool and then filtered toyield a pale brown solid (3.1 g). The filtrate was concentrated todryness and then triturated with diethyl ether (40 mL) to afford anoff-white solid (4.80 g). The two batches of solid were combined andtriturated with methanol (30 mL) to afford the title compound as a palebrown solid (4.8 g, 38% yield). LCMS (Method E): RT=3.48 min, m/z: 365[M+H⁺].

Step 2. 2-Bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzimidoylchloride

A stirred solution of2-bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzamide (4.8 g,13.2 mmol) in thionyl chloride (100 mL) was heated at 100° C. for 18hours under a nitrogen atmosphere. After cooling to room temperature,the volatiles were removed under reduced pressure and the resultantresidue was purified by column chromatography on silica gel eluting with30% diethyl ether in pentane to afford the title compound as a paleyellow solid (4.2 g, 83% yield). LCMS (Method D): RT=4.47 min, m/z: 383[M+H⁺].

Step 3. 2-(2-Bromo-6-chlorophenyl)-4-chlorothiazolo[5,4-c]pyridine

A stirred solution of2-bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzimidoyl chloride(4.2 g, 11.0 mmol), thiourea (2.5 g, 33.0 mmol) and pyridine (3.1 mL,38.4 mmol) in isopropanol (50 mL) under a nitrogen atmosphere was heatedunder reflux for 3 hours. Et₃N (7.6 mL, 54.6 mmol) was added and thereaction mixture was heated under reflux for 1.5 hours. After cooling toroom temperature, the volatiles were removed under reduced pressure. Theresultant residue was triturated with water (100 mL) and then boiled inisopropanol (15 mL) for 10 minutes. After cooling to room temperature,the resultant solid was collected by filtration and then purified bycolumn chromatography on silica gel eluting with 25% diethyl ether inpentane to afford the title compound as a colourless solid (2.1 g, 53%).LCMS (Method E): RT=4.16 min, m/z: 361 [M+H⁺].

Step 4. 3-Chloro-2-(4-chlorothiazolo[5,4-c]pyridine-2-yl)-benzonitrile

A stirred mixture of2-(2-bromo-6-chlorophenyl)-4-chlorothiazolo[5,4-c]pyridine (1.48 g, 4.11mmol) and copper(I) cyanide (0.45 g, 5.0 mmol) in NMP (20 mL) was heatedat 150° C. for 20 minutes. After cooling to room temperature, themixture was poured into water (250 mL) and the insoluble material wascollected by filtration. The solid was then suspended in EtOAc (300 mL)and, after vigorous stirring, was collected by filtration. The filtratewas concentrated under reduced pressure and the resultant residue waspurified by column chromatography on silica gel eluting with 25-33%diethyl ether in pentane followed by 0-10% MeOH in DCM to afford thetitle compound as a pale yellow solid (0.364 g, 29% yield). LCMS (MethodE): RT=3.59 min, m/z: 306 [M+H⁺].

Step 5. 2-(4-Bromothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile

Trimethylsilyl bromide (1 mL) was added to a solution of3-chloro-2-(4-chlorothiazolo[5,4-c]pyridine-2-yl)-benzonitrile (0.364 g,1.18 mmol) in propionitrile (15 mL) at room temperature under a nitrogenatmosphere. The reaction mixture was heated at 85° C. for 2 hours andthen the volatiles were removed under reduced pressure. The resultantresidue was purified by column chromatography on silica gel eluting with0-100% methanol in DCM to afford the title compound as a pale brownsolid (230 mg, 56% yield). LCMS (Method D): RT=3.70 min, m/z: 337[M+H⁺].

Step 6. (6-Azidopyrimidin-4-yl)-bis-carbamic acid tert-butyl ester

To a mixture of (6-chloropyrimidin-4-yl)-bis-carbamic acid tert-butylester (2.0 g, 6.0 mmol) in DMF (10 mL) was added sodium azide (780 mg,12.0 mmol). The resultant mixture was heated at 70° C. for 4 hours.After allowing to cool to room temperature, the crude mixture waspartitioned between water and EtOAc. The organic layer was washed withbrine (×2), dried (Na₂SO₄) and concentrated to dryness. The resultantresidue was purified by column chromatography on silica gel eluting with20% EtOAc in cyclohexane to afford the title compound as a pale yellowsolid (1.33 g, 66% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.63 (s, 1H),7.18 (s, 1H), 1.53 (s, 18H).

Step 7. (6-Aminopyrimidin-4-yl)-bis-carbamic acid tert-butyl ester

A suspension of (6-azidopyrimidin-4-yl)-bis-carbamic acid tert-butylester (1.33 g, 4.0 mmol) and 5% Pd/C (1.0 g) in IMS (10 mL) and EtOAc (3mL) was stirred under a hydrogen atmosphere for 18 hours at roomtemperature. The reaction mixture was then filtered through Celite®washing with EtOAc. The filtrate was concentrated to dryness underreduced pressure and the resultant residue was titurated with diethylether to afford the title compound as a white solid (1.21 g, 95%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 6.96 (br s, 2H), 6.49 (s, 1H),1.45 (s, 18H).

Step 8.{6-[2-(2-Chloro-6-cyanophenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of 2-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile(0.105 g, 0.30 mmol), (6-aminopyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (77 mg, 0.36 mmol), XantPhos (0.018 g, 0.03 mmol) andCs₂CO₃ (247 mg, 0.75 mmol) in dioxane (2.5 mL) was degassed with astream of argon. Pd₂(dba)₃ (0.014 g, 0.015 mmol) was added and thereaction mixture was heated at 80° C. for 3 hours in a sealed vial.Additional amounts of XantPhos (0.018 g), Pd₂(dba)₃ (0.015 g),(6-aminopyrimidin-4-yl)-bis-carbamic acid tert-butyl ester (100 mg) anddioxane (1 mL) were added and the mixture was degassed with a stream ofargon. Heating at 80° C. was continued for 18 hours. After cooling toroom temperature, the crude reaction mixture was filtered throughCelite® washing with DCM (100 mL). The filtrate was concentrated todryness under reduced pressure and the resultant residue was purified bycolumn chromatography on silica gel eluting with 0-80% EtOAc in pentanefollowed by 0-30% EtOAc in DCM to afford the title compound as a yellowoil (56 mg, 32% yield). LCMS (Method F): RT=4.20 min, m/z: 580 [M+H⁺].

Step 9.2-[4-(6-Aminopyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrile

A mixture of{6-[2-(2-chloro-6-cyanophenyl)thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (53 mg, 0.09 mmol) in HCl (4N in dioxane, 5 mL)was heated at 50° C. under a nitrogen atmosphere for 1 hour and then wasstirred at room temperature for 18 hours. The volatiles were removedunder reduced pressure and the resultant residue was triturated withisopropanol to afford the title compound as a white solid (33 mg, 88%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.57-8.47 (m, 2H),8.18-8.08 (m, 2H), 7.98 (d, J=5.7 Hz, 1H), 7.88 (t, J=8.1 Hz, 1H), 7.06(br s, 1H). LCMS (Method C): RT=2.86 min, m/z: 380 [M+H⁺].

Example 1463-Chloro-2-[4-(6-hydroxymethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

Step 1. 2-Chloro-3-fluoro-4-iodopyridine

A solution of lithium di-isopropylamide (2N intetrahydrofuran/ethylbenzene/heptane, 155 mL, 310 mmol) was addeddropwise over 40 minutes to solution of 2-chloro-3-fluoropyridine (31.0g, 235 mmol) in tetrahydrofuran (200 mL) at −70° C. and the resultingmixture stirred for 4 hours. A solution of iodine (69.0 g, 200 mmol) intetrahydrofuran (100 mL) was added dropwise over 30 minutes and theresultant mixture was stirred for 30 minutes at −70° C. then allowed towarm to room temperature over 1 hour. The reaction mixture was pouredonto aqueous sodium metabisulphite solution (20% w/v, 2 L) and extractedwith diethyl ether (3×300 mL). The combined organic extracts were washedwith aqueous sodium metabisulphite solution (20% w/v, 2 L) and water(200 mL), dried over Na₂SO₄ and evaporated under reduced pressure toyield an oil. The resultant oil was triturated with diethyl ether toyield the title compound as a red/brown solid (28 g, 46% yield). ¹H NMR(400 MHz, CDCl₃): δ 7.87 (d, J=5.0 Hz, 1H), 7.66 (ddd, J=5.0, 4.0, 0.4Hz, 1H).

Step 2. 2-Chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide

A mixture of 2-chloro-3-fluoro-4-iodopyridine (4.78 g, 18.6 mmol),2-chloro-6-nitrobenzamide (3.91 g, 19.5 mmol), ethane-1,2-diamine (0.2mL, 2.97 mmol), copper(I) iodide (0.57 g, 2.97 mmol) and K₃PO₄ (7.90 g,37.2 mmol) in dioxane (80 mL), was degassed with a stream of argon andthe reaction mixture was then heated under reflux for 4 hours. Aftercooling to room temperature, the crude reaction mixture was filteredthrough Celite® washing with dioxane. The filtrate was concentrated todryness under reduced pressure and the resultant residue was purified bycolumn chromatography on silica gel eluting with 0-100% ethyl acetate inpetroleum ether (40-60° C.), to afford the title compound as a paleyellow solid (1.87 g, 31% yield). ¹H NMR (400 MHz, DMSO-d₆): δ11.42-11.37 (br s, 1H), 8.35-8.24 (m, 3H), 8.08 (dd, J=1.1, 8.1 Hz, 1H),7.81 (t, J=8.2 Hz, 1H).

Step 3. 2-Chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzimidoylchloride

A stirred solution of2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide (4.27 g,12.9 mmol) in thionyl chloride (60 mL) was heated at 85° C. for 2 daysunder a nitrogen atmosphere. After cooling to room temperature, thevolatiles were removed under reduced pressure and the resultant residuewas purified by column chromatography on silica gel eluting with 0-30%ethyl acetate in petroleum ether (40-60° C.), to afford the titlecompound as a cream solid (3.90 g, 87% yield). ¹H NMR (400 MHz, CDCl₃):δ 8.27-8.20 (m, 2H), 7.88 (dd, J=1.1, 8.1 Hz, 1H), 7.66 (t, J=8.2 Hz,1H), 6.95 (t, J=5.2 Hz, 1H).

Step 4. 4-Chloro-2-(2-chloro-6-nitrophenyl)thiazolo[5,4-c]pyridine

A stirred suspension of2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide (3.90 g,11.2 mmol), thiourea (3.40 g, 44.8 mmol) and pyridine (3.1 mL, 38.1mmol) in isopropanol (35 mL) under a nitrogen atmosphere, was heatedunder reflux for 4 hours. After this time, Et₃N (9.4 mL, 67.2 mmol) wasadded and the reaction mixture was heated under reflux for 16 hours.After cooling to room temperature, the volatiles were removed underreduced pressure. The crude residue was triturated with ethyl acetateand the solid was removed by filtration. The resultant filtrate waswashed with 10% citric acid, brine, dried over MgSO₄ and evaporatedunder reduced pressure to afford the title compound as a pale orangesolid (3.55 g, 97%). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (d, J=5.5 Hz, 1H),8.13 (dd, J=1.2, 8.4 Hz, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.87 (dd, J=1.2,8.3 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H).

Step 5. 3-Chloro-2-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenylamine

Iron powder (6.08 g, 109 mmol) was added to a solution of4-chloro-2-(2-chloro-6-nitrophenyl)thiazolo[5,4-c]pyridine (3.55 g, 10.9mmol) in AcOH (100 mL). The reaction mixture was heated at 100° C. for30 minutes and then allowed to cool to room temperature. The volatileswere removed under reduced pressure and the resultant residue wasdissolved in DCM/MeOH and filtered through Celite® washing further withMeOH. The combined washings were concentrated under reduced pressure andthe resultant residue was triturated with 10% MeOH in DCM to afford thetitle compound as an orange/red solid (2.55 g, 79% yield). ¹H NMR (400MHz, CDCl₃): δ 8.44 (d, J=5.6 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.16 (t,J=7.9 Hz, 1H), 6.89 (dd, J=1.2, 7.8 Hz, 1H), 6.73 (dd, J=1.2, 8.3 Hz,1H), 6.14 (br s, 2H).

Step 6. 3-Chloro-2-(4-chlorothiazolo[5,4-c]pyridine-2-yl)-benzonitrile

A solution of sodium nitrite (334 mg, 4.85 mmol) in water (4.8 mL) wasadded dropwise to a suspension of3-chloro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-phenylamine (1.42 g,4.8 mmol) in CH₃CN (23.6 mL), conc. HCl (12N, 4.8 mL) and water (21.3mL) at 0° C. The resultant mixture was stirred between 0 and 5° C. for 1hour.

Simultaneously, in a separate flask, CuSO₄.5H₂O (1.44 g, 5.76 mmol) inwater (5.76 mL) was added dropwise to a solution of KCN (1.44 g, 22.1mmol) in water (7.8 mL) at 0° C., followed by toluene (15.8 mL) and thereaction mixture was heated at 60° C. for 1 hour.

The pH of the diazonium suspension was adjusted to 6-7 by carefuladdition of a saturated solution of NaHCO₃ (˜40 mL) at 0° C. Theresultant mixture was then added dropwise over 20 minutes to the coppercyanide mixture at 60° C. The resultant suspension was heated at 70° C.for 50 minutes and then allowed to cool to room temperature. Thereaction mixture was filtered through Celite® washing with EtOAc (200mL). The combined organic extracts were washed with brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The cruderesidue was firstly purified by column chromatography on silica geleluting with 0-20% EtOAc in petroleum ether (40-60° C.), then by asecond column eluting with 0-1% MeOH in DCM to afford the title compoundas a yellow solid (574 mg, 39% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.54(d, J=5.6 Hz, 1H), 8.02 (d, J=5.6 Hz, 1H), 7.85-7.80 (m, 2H), 7.63 (t,J=8.1 Hz, 1H).

Step 7. 3-Chloro-2-(4-chlorothiazolo[5,4-c]pyridine-2-yl)-benzonitrile

A mixture of3-chloro-2-(4-chlorothiazolo[5,4-c]pyridin-2-yl)benzonitrile (100 mg,0.33 mmol), (6-aminopyrimidin-4-yl)methanol (45 mg, 0.36 mmol), XantPhos(0.019 g, 0.033 mmol) and Cs₂CO₃ (215 mg, 0.66 mmol) in dioxane (4 mL)was degassed with a stream of argon. Pd₂(dba)₃ (0.015 g, 0.0163 mmol)was added and the reaction mixture was heated at 85° C. for 18 hours.After cooling to room temperature, the crude mixture was filteredthrough Celite®, washing with DCM/MeOH and the filtrate was concentratedto dryness under reduced pressure. The resultant residue was purified bycolumn chromatography on silica gel, eluting with 0-3% MeOH in EtOAc,and then by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 30minute gradient 20-80%, 0.1% HCO₂H in MeOH/H₂O) to afford the titlecompound as an off-white solid (30 mg, 23% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 10.80 (br s, 1H), 8.64 (d, J=1.2 Hz, 1H), 8.49 (d, J=5.6 Hz,1H), 8.15-8.07 (m, 2H), 7.90-7.82 (m, 2H), 7.76 (br s, 1H), 5.58 (t,J=5.7 Hz, 1H), 4.49 (d, J=4.8 Hz, 2H). LCMS (Method C): RT=2.97 min,m/z: 395 [M+H⁺].

Example 1472-[4-(6-Amino-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrilehydrochloride salt

Step 1. (6-Azido-2-methylpyrimidin-4-yl)-bis-carbamic acid tert-butylester

To a mixture of (6-chloro-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (2.0 g, 5.8 mmol) in DMSO (10 mL) was added sodiumazide (757 mg, 11.6 mmol). The resultant mixture was heated at 50° C.for 16 hours. After cooling to room temperature, the crude mixture waspartitioned between water and EtOAc. The aqueous layer was washed withEtOAc (×2). The combined organic extracts were washed with brine (×2),dried (Na₂SO₄) and concentrated to dryness to afford the title compoundas an oil (1.64 g, 80% yield). LCMS (Method D): RT=3.76 min, m/z: 351[M+H⁺].

Step 2. (6-Amino-2-methylpyrimidin-4-yl)-bis-carbamic acid tert-butylester

A suspension of (6-azido-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (1.64 g, 4.7 mmol) and 5% Pd/C (0.5 g) in IMS (36 mL)and EtOAc (12 mL) was stirred under a hydrogen atmosphere for 18 hoursat room temperature. The reaction mixture was then filtered throughCelite® washing with EtOAc. The filtrate was concentrated to drynessunder reduced pressure and the resultant residue was purified by columnchromatography on silica gel eluting with 0-60% EtOAc in petroleum ether(40-60° C.) to afford the title compound as a white solid (0.74 g, 49%).LCMS (Method D): RT=2.72 min, m/z: 325 [M+H⁺].

Step 3.{6-[2-(2-Chloro-6-cyanophenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-2-methylpyrimidin-4-yl}-bis-carbamicacid tert-butyl ester

A mixture of2-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile (0.27 g,0.88 mmol), (6-amino-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (314 mg, 0.97 mmol), XantPhos (0.051 g, 0.09 mmol) andCs₂CO₃ (722 mg, 2.20 mmol) in dioxane (10 mL) was degassed with a streamof argon. Pd₂(dba)₃ (0.040 g, 0.044 mmol) was added and the reactionmixture was heated at 80° C. for 16 hours in a sealed vial. Aftercooling to room temperature, the crude reaction mixture was filteredthrough Celite® washing with DCM (100 mL). The filtrate was concentratedto dryness under reduced pressure and the resultant residue was purifiedby column chromatography on silica gel eluting with 0-60% EtOAc inpentane followed by 0-25% EtOAc in DCM to afford the title compound as ayellow oil (305 mg, 59% yield). LCMS (Method D): RT=4.38 min, m/z: 594[M+H⁺].

Step 4.2-[4-(6-Amino-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3-chlorobenzonitrilehydrochloride salt

A mixture of{6-[2-(2-chloro-6-cyanophenyl)-thiazolo[5,4-c]pyridin-4-ylamino]-2-methylpyrimidin-4-yl}-bis-carbamicacid tert-butyl ester (305 mg, 0.51 mmol) in HCl (4N in dioxane, 10 mL)was heated at 50° C. under a nitrogen atmosphere for 5 hours. Aftercooling to room temperature, the volatiles were removed under reducedpressure and the resultant residue was triturated with isopropanol toafford the title compound as an off-white solid (236 mg, quantitativeyield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.44 (br s, 1H), 8.53 (d, J=5.5Hz, 1H), 8.16-8.10 (m, 2H), 7.97 (d, J=5.5 Hz, 1H), 7.87 (t, J=8.1 Hz,1H), 7.15 (br s, 1H), 4.05 (br s, 3H), 3.57 (s, 3H). LCMS (Method C):RT=2.92 min, m/z: 394 [M+H⁺].

Example 1483-Chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

Step 1. 2-Chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide

A solution of 2-chloro-6-nitrobenzoyl chloride (7.63 g, 34.7 mmol) indioxane (12 mL) was added dropwise over 5 minutes to a solution of3,5-difluoropyridin-4-ylamine (3.77 g, 29.0 mmol) in pyridine (40 mL) atroom temperature under argon. The reaction mixture was stirred at roomtemperature for 19 hours then the volatiles were removed under reducedpressure. To the resultant residue, HCl (1N, 60 mL) was added and thesuspension was sonicated and then stirred at room temperature for 30minutes. The resultant solid was filtered to afford a mixture of2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide {LCMS (Method D):RT=2.76 min, m/z: 314 [M+H⁺]} and2-chloro-N-(2-chloro-6-nitrobenzoyl)-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide{LCMS (Method D): RT=3.77 min, m/z: 498 [M+H⁺]}.

NaOH (1N, 60 mL) was added to a suspension of this solid in MeOH (60 mL)at room temperature under argon. The reaction mixture was heated at 50°C. for 1.5 hours, allowed to cool to room temperature, and then theorganic solvent was removed in vacuo. The resultant mixture was madeacidic (pH 2-3) by addition of 12N HCl and was then cooled to 0° C. Theresultant solid was filtered and dried to afford the title compound as apale yellow solid (5.25 g, 58% yield) which was used in the followingstep without further purification. LCMS (Method D): RT=2.76 min, m/z:314 [M+H⁺].

Step 2. 2-Chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoylchloride

A mixture of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide(5.25 g, 16.7 mmol) in thionyl chloride (40 mL) was heated under refluxfor 18 hours under a nitrogen atmosphere. After cooling to roomtemperature, the volatiles were removed under reduced pressure and theresultant residue was azeotroped with toluene (×3) to afford the titlecompound as a yellow/brown solid (5.5 g, quantitative). LCMS (Method D):RT=3.77 min, m/z: 332 [M+H⁺].

Step 3. 2-(2-Chloro-6-nitrophenyl)-7-fluorothiazolo[5,4-c]pyridine

A suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoylchloride (5.53 g, 16.6 mmol), thiourea (5.05 g, 0.066 mol) and pyridine(6.7 mL, 83 mmol) in isopropanol (90 mL), under nitrogen, was heatedunder reflux for 6 hours. After this time, Et₃N (14 mL, 100 mmol) wasadded over 5 minutes and the reaction mixture was heated under refluxfor 18 hours. Upon cooling to room temperature, the volatiles wereremoved under reduced pressure and the resultant residue was partitionedbetween water and EtOAc. The aqueous phase was further extracted withEtOAc (×2) and the combined organic layers were dried (Na₂SO₄) andconcentrated to dryness. The resultant residue was purified by columnchromatography on silica gel eluting with 0-80% EtOAc in pentanefollowed by 0-50% EtOAc in DCM to afford the title compound as a yellowsolid (2.55 g, 50% yield). LCMS (Method D): RT=3.29 min, m/z: 310[M+H⁺].

Step 4. 3-Chloro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-phenylamine

Iron powder (7.95 g, 141 mmol) was added to a solution of2-(2-chloro-6-nitrophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.35 g, 14.1mmol) in AcOH (130 mL). The reaction mixture was heated at 100° C. for30 minutes and then allowed to cool to room temperature. The volatileswere removed under reduced pressure and the resultant residue wasdissolved in DCM/MeOH and filtered through Celite® washing the filterpad thoroughly with further DCM/MeOH. The filtrate was concentratedunder reduced pressure and the resultant residue was purified by columnchromatography on silica gel eluting with 0-5% MeOH in DCM to afford thetitle compound as a yellow solid (3.63 g, 92% yield). ¹H NMR (300 MHz,CDCl₃): δ 9.03 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H),6.89 (d, J=7.8 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 6.28 (br s, 2H). LCMS(Method D): RT=3.51 min, m/z: 280 [M+H⁺].

Step 5. 3-Chloro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile

Sodium nitrite (0.89 g, 12.9 mmol) in water (17 mL) was added dropwiseto a suspension of3-chloro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-phenylamine (3.43 g,12.3 mmol) and 37% hydrochloric acid (16.1 mL) in water (34 mL) andacetonitrile (62 mL) at 0° C. The resultant mixture was stirred at 0° C.for 1.5 hours until all of the solid had dissolved.

Simultaneously, in a separate flask, a solution of CuSO₄.5H₂O (3.77 g,15.1 mmol) in water (17 mL) was added dropwise to a solution of KCN(3.77 g, 58.3 mmol) in water (21 mL) at 0° C. Toluene (41 mL) was thenadded and the reaction mixture was heated at 60° C. for 1.5 hours.

The diazonium salt solution, still at 0° C., was treated cautiously withaqeuous sodium bicarbonate to achieve pH 6-7. The resultant mixture wasthen added, dropwise over 15 min, to the copper cyanide mixture at 60°C. The reaction mixture was heated at 70° C. for 1.5 hours, allowed tocool to room temperature and was then partitioned between ethyl acetateand water and the aqueous layer was extracted with ethyl acetate (×3).The combined organic extracts were dried (sodium sulphate) andevaporated. The crude product was triturated twice with 1:1 diethylether/cyclohexane (100 mL) and the solid was filtered off and driedunder vacuum to give the title compound as an off-white solid (2.31 g).The trituration liquors were evaporated and the crude residue waspurified by column chromatography on silica gel, eluting with 0-40%ethyl acetate in cyclohexane to give a further crop of the titlecompound as an off-white solid (0.49 g). Combined yield: (2.80 g, 79%).¹H NMR (300 MHz, DMSO-d₆): δ 9.44 (s, 1H), 8.80-8-77 (m, 1H), 8.13 (t,J=8.0 Hz, 2H), 7.88 (t, J=8.0 Hz, 1H). LCMS (Method F): RT=3.10 min,m/z: 290 [M+H⁺].

Step 6.3-Chloro-2-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile

To a solution of3-chloro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (880 mg,3.04 mmol) in DCM (15 mL) and methyltrioxorhenium(VII) (76 mg, 0.3 mmol)under argon was added 27.5% aq. hydrogen peroxide (0.68 mL, 6.08 mmol).The reaction mixture was stirred at room temperature for 72 hours. Thecrude mixture was diluted with DCM (40 mL) and MeOH (10 mL) and washedwith water (60 mL). The aqueous phase was extracted with EtOAc and thecombined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure to afford the title compound as ayellow solid (930 mg, quantitative). LCMS (Method D): RT=2.51 min, m/z:306 [M+H⁺].

Step 7.3-Chloro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile

To a suspension of3-chloro-2-(7-fluoro-5-oxy-thiazolo[5,4-c]pyridin-2-yl)-benzonitrile(2.11 g, 6.92 mmol) in 1,2-dichloroethane (34 mL) was added phosphorusoxychloride (2.0 mL, 22.2 mmol). The reaction mixture was heated at 70°C. for 16 hours. Upon cooling, the resultant mixture was treatedcautiously with aqueous sodium bicarbonate to achieve pH 6-7, and thenextracted with dichloromethane (×5). The combined organic extracts weredried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel eluting with0-50% ethyl acetate in cyclohexane to afford the title compound as awhite solid 1.43 g (64% yield). ¹H NMR (300 MHz, CDCl₃): δ 8.42 (d,J=1.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.66 (t, J=8.0 Hz, 1H).

Step 8.2-(4-Bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile

Trimethylsilyl bromide (1.8 mL, 13.2 mmol) was added to a suspension of3-chloro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile(1.43 g, 4.40 mmol) in propionitrile (40 mL) at room temperature, underargon. The reaction mixture was heated at 50° C. for 7 hours. Thereaction mixture was adjusted to pH 7 by careful addition of a saturatedaqueous solution of sodium bicarbonate. The resultant mixture wasextracted with DCM (×3) and the combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure to afford the titlecompound as an off-white solid (1.65 g, 100% yield). ¹H NMR (300 MHz,CDCl₃): δ 8.42 (d, J=1.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.66 (t, J=8.0 Hz,1H).

Step 9.3-Chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

A mixture of2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile(0.110 g, 0.30 mmol), 6-methylpyrimidin-4-ylamine (35 mg, 0.32 mmol),XantPhos (0.018 g, 0.03 mmol) and Cs₂CO₃ (247 mg, 0.75 mmol) in dioxane(2.5 mL) was degassed with a stream of argon. Pd₂(dba)₃ (0.014 g, 0.015mmol) was added and the reaction mixture was heated at 80° C. for 2hours in a sealed vial. After cooling to room temperature, the crudereaction mixture was filtered through Celite® washing with EtOAc (50mL). The filtrate was concentrated to dryness under reduced pressure.The resultant residue was purified by column chromatography on silicagel eluting with 0-100% EtOAc in DCM, then triturated with diethyl ether(×2), to afford the title compound as a pale yellow solid (43 mg, 36%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.73 (d, J=1.2 Hz, 1H), 8.34 (d,J=1.8 Hz, 1H), 7.86-7.76 (m, 3H), 7.66 (t, J=8.0 Hz, 1H), 7.57 (br s,1H), 2.56 (s, 3H). LCMS (Method C): RT=3.31 min, m/z: 397 [M+H⁺].

Example 1493-Chloro-2-[7-fluoro-4-(6-hydroxymethyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

A mixture of2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile(0.35 g, 0.95 mmol), (6-aminopyrimidin-4-yl)methanol (125 mg, 1.0 mmol),XantPhos (0.055 g, 0.095 mmol) and Cs₂CO₃ (780 mg, 2.38 mmol) in dioxane(11 mL) was degassed with a stream of argon. Pd₂(dba)₃ (0.048 g, 0.047mmol) was added and the reaction mixture was heated at 80° C. for 6hours in a sealed vial. After cooling to room temperature, the crudereaction mixture was diluted with EtOAc (100 mL) and water (20 mL) andthe resultant mixture was filtered through Celite® washing with EtOAc(50 mL). The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated under reduced pressure The resultant residuewas purified by column chromatography on silica gel eluting with 0-10%MeOH in DCM, then triturated with diethyl ether (×2), to afford thetitle compound as a pale yellow solid (203 mg, 52% yield). ¹H NMR (400MHz, DMSO-d₆): δ 10.79 (br s, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.52 (d,J=1.8 Hz, 1H), 8.16-8.08 (m, 2H), 7.86 (t, J=8.0 Hz, 1H), 7.58 (s, 1H),5.57 (t, J=5.7 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H). LCMS (Method C): RT=3.29min, m/z: 413 [M+H⁺].

Example 1503-Fluoro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrilehydrochloride salt

Step 1. 2-Fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide

A solution of 2-fluoro-6-nitrobenzoyl chloride (10.97 g, 52.4 mmol) indioxane (20 mL) was added dropwise over 5 minutes to a solution of3,5-difluoropyridin-4-ylamine (6.19 g, 47.6 mmol) in pyridine (80 mL) atroom temperature under argon. The reaction mixture was stirred at roomtemperature for 18 hours then the volatiles were removed under reducedpressure. To the resultant residue, HCl (1N, 100 mL) was added and thesuspension was sonicated and then stirred at room temperature for 30minutes. The resultant solid was filtered and dried to afford a mixtureof 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide {LCMS (MethodD): RT=2.67 min, m/z: 298 [M+H⁺]} and2-chloro-N-(2-fluoro-6-nitrobenzoyl)-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide{LCMS (Method D): RT=3.63 min, m/z: 465[M+H⁺]}.

NaOH (1N, 100 mL) was added to a suspension of this solid in MeOH (100mL) at room temperature under argon. The reaction mixture was heated at60° C. for 1.5 hours, allowed to cool to room temperature, and then theorganic solvent was removed in vacuo. The resultant mixture was madeacidic (pH 2-3) by addition of 12N HCl and was then cooled to 0° C. Theresultant solid was filtered and dried to afford the title compound as apale yellow solid (10.81 g, 76% yield). LCMS (Method D): RT=2.66 min,m/z: 298 [M+H⁺].

Step 2. 2-Fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoylchloride

A mixture of 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide(10.81 g, 36.4 mmol) in thionyl chloride (95 mL) was heated under refluxfor 3 days under a nitrogen atmosphere. After cooling to roomtemperature, the volatiles were removed under reduced pressure and theresultant residue was azeotroped with toluene (×3) to afford the titlecompound as a yellow/pale brown solid (12.05 g, quantitative). LCMS(Method D): RT=3.64 min, m/z: 316 [M+H⁺].

Step 3. 2-(2-Fluoro-6-nitrophenyl)-7-fluorothiazolo[5,4-c]pyridine

A suspension of 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoylchloride (12.05 g, 36.4 mmol), thiourea (12.05 g, 159 mmol) and pyridine(16 mL, 200 mmol) in isopropanol (200 mL) under a nitrogen atmospherewas heated under reflux for 4 hours. Et₃N (33.2 mL, 239 mmol) was addedover 5 minutes and the reaction mixture was heated under reflux for 18hours. After cooling to room temperature, the volatiles were removedunder reduced pressure and the resultant residue was partitioned betweenwater and EtOAc. The aqueous phase was further extracted with EtOAc (×5)and the combined organic layers were dried (Na₂SO₄) and concentrated todryness. The resultant residue was purified by column chromatography onsilica gel eluting with 0-50% EtOAc in cyclohexane to afford the titlecompound as a yellow solid (4.33 g, 41% yield). LCMS (Method D): RT=3.21min, m/z: 294 [M+H⁺].

Step 4. 3-Fluoro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-phenylamine

Iron powder (8.29 g, 148 mmol) was added to a solution of2-(2-fluoro-6-nitrophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.33 g, 14.8mmol) in AcOH (144 mL). The reaction mixture was heated at 100° C. for30 minutes and then allowed to cool to room temperature. The volatileswere removed under reduced pressure and the resultant residue wasdissolved in DCM/MeOH and filtered through Celite® washing the filterpad thoroughly with further DCM/MeOH. The filtrate was concentratedunder reduced pressure and the resultant residue was purified by columnchromatography on silica gel eluting with 0-2% MeOH in DCM, thentriturated with DCM and then dried to afford the title compound as ayellow solid (2.23 g, 57% yield). LCMS (Method D): RT=3.62 min, m/z: 264[M+H⁺].

Step 5. 3-Fluoro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile

Sodium nitrite (0.54 g, 7.82 mmol) in water (7.0 mL) was added dropwiseto a suspension of3-fluoro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-phenylamine (2.03 g,7.72 mmol) and 37% hydrochloric acid (9.54 mL) in water (20 mL) andacetonitrile (36 mL) at 0° C. The resultant mixture was stirred at 0° C.for 1 hour until all of the solid had dissolved.

Simultaneously, in a separate flask, a solution of CuSO₄.5H₂O (2.34 g,9.24 mmol) in water (10 mL) was added dropwise to a solution of KCN(2.23 g, 34.5 mmol) in water (12 mL) at 0° C. Toluene (24 mL) was thenadded and the reaction mixture was heated at 60° C. for 1 hour.

The diazonium salt solution, still at 0° C., was treated cautiously withaqeuous sodium bicarbonate to achieve pH 6-7. The resultant mixture wasthen added, dropwise over 15 min, to the copper cyanide mixture at 60°C. The reaction mixture was heated at 70° C. for 1.5 hours, allowed tocool to room temperature and was then partitioned between ethyl acetateand water and the aqueous layer was extracted with ethyl acetate (×3).The combined organic extracts were dried (sodium sulphate) andevaporated. The crude product was triturated twice with 1:1 diethylether/cyclohexane (40 mL) and the solid was filtered off and dried undervacuum to give the title compound as a yellow solid (1.09 g, 52%). LCMS(Method C): RT=3.15 min, m/z: 274 [M+H⁺].

Step 6.3-Fluoro-2-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile

To a solution of3-fluoro-2-(7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (1.09 g,3.99 mmol) in DCM (14 mL) and methyltrioxorhenium(VII) (100 mg, 0.41mmol) under argon was added 27.5% aq. hydrogen peroxide (1.18 mL, 9.47mmol). The reaction mixture was stirred at room temperature for 72 hoursadding further portions of methyltrioxorhenium(VII) (100 mg, 0.41 mmol)and 27.5% aq. hydrogen peroxide (1.18 mL, 9.47 mmol) after each 24 hourperiod. The crude mixture was diluted with DCM (60 mL) and MeOH (15 mL)and washed with aqeuous sodium bicarbonate (60 mL). The aqueous phasewas extracted with DCM/MeOH and the combined organic extracts were dried(Na₂SO₄) and concentrated under reduced pressure to afford the titlecompound as a pale yellow solid (1.01 g, 88%). LCMS (Method F): RT=2.32min, m/z: 290 [M+H⁺].

Step 7.3-Fluoro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile

To a suspension of3-fluoro-2-(7-fluoro-5-oxy-thiazolo[5,4-c]pyridin-2-yl)-benzonitrile(1.13 g, 3.90 mmol) in 1,2-dichloroethane (20 mL) was added phosphorusoxychloride (1.14 mL, 12.5 mmol). The reaction mixture was heated at 70°C. for 18 hours. Upon cooling, the resultant mixture was treatedcautiously with aqueous sodium bicarbonate to achieve pH 6-7, and thenextracted with 20% MeOH in dichloromethane (×5). The combined organicextracts were dried (Na₂SO₄) and concentrated under reduced pressure.The crude product was purified by column chromatography on silica geleluting with 0-50% ethyl acetate in cyclohexane to afford the titlecompound as a white solid 0.70 g (61% yield). LCMS (Method D): RT=3.82min, m/z: 308 [M+H⁺].

Step 8.2-(4-Bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-fluorobenzonitrile

Trimethylsilyl bromide (0.92 mL, 6.85 mmol) was added to a suspension of3-fluoro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile(0.70 g, 2.28 mmol) in propionitrile (20 mL) at room temperature, underargon. The reaction mixture was heated at 50° C. for 16 hours. Thereaction mixture was adjusted to pH 7 by careful addition of a saturatedaqueous solution of sodium bicarbonate. The resultant mixture wasextracted with DCM (×3) and the combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure. The resultant solidwas triturated with diethyl ether and dried under vacuum to afford thetitle compound as an off-white solid (0.76 g, 95% yield). LCMS (MethodD): RT=3.87 min, m/z: 352 [M+H⁺].

Step 9.3-Fluoro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrilehydrochloride salt

A mixture of2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile(0.100 g, 0.28 mmol), 6-methylpyrimidin-4-ylamine (33 mg, 0.30 mmol),XantPhos (0.016 g, 0.028 mmol) and Cs₂CO₃ (173 mg, 0.53 mmol) in dioxane(2.0 mL) was degassed with a stream of argon. Pd₂(dba)₃ (0.013 g, 0.014mmol) was added and the reaction mixture was heated at 80° C. for 24hours in a sealed vial. After cooling to room temperature, the crudereaction mixture was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc (×3) and the combined organic extractswere dried (Na₂SO₄) and concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 50-100% EtOAc in cyclohexane. The resultant residue wasdissolved in DCM (10 mL) and HCl (1.25N in propan-2-ol, 0.1 mL) wasadded and the mixture was concentrated to dryness. The crude solidobtained was triturated with diethyl ether (×2), acetonitrile (×3) andcyclohexane (×3), before drying to afford the title compound as an offwhite solid (19 mg, 16% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (s,1H), 8.93 (s, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.08-8.02 (m, 1H), 7.99-7.89(m, 2H), 7.59 (s, 1H), 2.49 (s, 3H). LCMS (Method C): RT=3.12 min, m/z:381 [M+H⁺].

Example 1517-bromo-2-(2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

Step 1. N-(3-bromo-5-fluoropyridin-4-yl)-2-chloro-6-fluorobenzamide

To a solution of 3-bromo-5-fluoro-pyridin-4-amine (20.0 mmol, 3.82 g) inDMF (40 mL) was added NaH (40.0 mmol, 1.6 g). The mixture was stirred atroom temperature for 30 min, then cooled to 0° C. A soluntion of2-chloro-6-fluoro-benzoyl chloride (30.0 mmol, 5.79 g) in DCM (10 mL)was then added dropwise. The reaction mixture was stirred at roomtemperature for 16 hours. The reaction was then quenched with ice water,extracted with EtOAc. The combined organics were dried (Na₂SO₄),filtered and concentrated.

The resultant oil was dissolved in MeOH (40 mL) and THF (40 mL). 2N NaOH(30 mL) was added. The mixture was stirred at room temperature for 16hours. The volatile solvents were then removed under reduced pressure.Water (100 mL) was added. The aqueous layer was saturated with NaCl,extracted with CHCl₃/iPrOH (3/1). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude product was purified bysilica gel chromatography (0-8% EtOAc/DCM) to give the title compound asan off-white solid (3.4 g, 49% yield). ¹H NMR (400 MHz, DMSO) δ 11.07(s, 1H), 8.74 (s, 1H), 8.71 (s, 1H), 7.59 (dd, J=14.8, 7.8 Hz, 1H), 7.47(d, J=8.1 Hz, 1H), 7.40 (t, J=8.6 Hz, 1H). LCMS (ESI) m/z 348.9 [M+H⁺].

Step 2. 7-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine

To a suspension ofN-(3-bromo-5-fluoro-4-pyridyl)-2-chloro-6-fluoro-benzamide (6.891 mmol,2.395 g) in 1,2-dichloroethane (100 mL) was added thionyl chloride (45mL). The mixture was heated at reflux for 3 days under nitrogen whenmonitoring the reaction by LCMS showed incomplete conversion. Morethionyl chloride (21 mL) was added. The reaction mixture was heated atreflux for additional 44 hours. The reaction mixture was thenconcentrate, azeotroped with toluene twice to give a light yellow solidwhich was used in the next step directly.

A mixture of(1Z)-N-(3-bromo-5-fluoro-4-pyridyl)-2-chloro-6-fluoro-benzimidoylchloride, thiourea (103.4 mmol, 7.869 g) and pyridine (137.8 mmol, 10.9g, 2.3 mL) in anhydrous isopropanol (50 mL) was heated at reflux for 17hours. Triethylamine (13.78 mmol, 1.395 g) was then added. The mixturewas heated at reflux for another 1 hour, cooled to room temperature. Asolid precipitated and was filtered off. The filtrate was concentratedto give a solid residue which was partitioned between EtOAc (150 mL) andwater (100 mL). The aqueous layer was extracted with EtOAc (100 mL).Combined organics were dried (Na₂SO₄), filtered and concentrated. Thecrude product was purified by silica gel chromatography (0-20%EtOAc/hexane) to give the title compound as an off-white solid (1.88 g,79% yield). LCMS (ESI) m/z 344.0 [M+H⁺].

Step 3: 7-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine5-oxide

To a solution of7-bromo-2-(2-chloro-6-fluoro-phenyl)thiazolo[5,4-c]pyridine (2.0 mmol,690 mg) in DCM (20 mL) was added mCPBA (5. 2 mmol, 890 mg). The mixturewas stirred at room temperature for 5 hours. A soution of 1 M Na₂SO₃ (10mL) was then added. The mixture was then stirred at room temperature for1 hour. A solution of sat. NaHCO₃ was added. The layers were separated.The aqueous layer was extracted with DCM. Then the combined organicswere dried (Na₂SO₄), filtered and concentrated to give the titlecompound as an off-white solid which was used in the next step withoutpurification. LCMS (ESI) m/z 360.9 [M+H⁺].

Step 4. 4,7-dibromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine

To a suspension of7-bromo-2-(2-chloro-6-fluoro-phenyl)-5-oxido-thiazolo[5,4-c]pyridin-5-ium(2.0 mmol, 720 mg) in 1,2-dichloroethane (30 mL) was added POBr₃ (8.0mmol, 2.3 g). The mixture was heated at 70° C. for 3 hours. The mixturewas cooled to room temperature, and sat. NaHCO₃ solution was added. Theaqueous layer was extracted with DCM. The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude product was purified bysilica gel chromatography (0-15% EtOAc/hexane) to give the titlecompound as a white solid (600 mg, 71% yield). ¹H NMR (400 MHz, CDCl₃) δ8.60 (s, 1H), 7.49 (dd, J=14.2, 8.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H),7.19 (t, J=8.7 Hz, 1H). LCMS (ESI) m/z 422.9 [M+H⁺].

Step 5:7-bromo-2-(2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

The mixture of4,7-dibromo-2-(2-chloro-6-fluoro-phenyl)thiazolo[5,4-c]pyridine (0.227mmol; 96 mg), 6-methylpyrimidin-4-amine (0.34 mmol, 37 mg), Pd₂(dba)₃(0.011 mmol, 10 mg), XantPhos (0.0227 mmol; 14 mg) and Cs₂CO₃ (0.4544mmol, 148 mg) in 1,4-dioxane (3 mL) was heated at 75° C. under nitrogenin an oil bath for 4.5 hours. The reaction mixture was then cooled toroom temperature, filtered through celite, washed with EtOAc. Thefiltrate was concentrated and the resulting crude product was purifiedby silica gel chromatography (30-100% EtOAc/hexane) to give the titlecompound as an off-white solid (80 mg, 78% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 10.76 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.77-7.68 (m, 1H),7.62 (d, J=8.1 Hz, 1H), 7.56-7.48 (m, 2H), 2.39 (s, 3H). LCMS (MethodB): RT=4.39 min, m/z 450.0 [M+H⁺].

Example 1522-(2-chloro-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridine-7-carbonitrile

A mixture of7-bromo-2-(2-chloro-6-fluoro-phenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine(0.15 mmol, 69 mg), Zn(CN)₂ (0.30 mmol, 36 mg), Pd₂(dba)₃ (0.015 mmol,13.8 mg), and dppf (0.030 mmol, 16.5 mg) in a 10 mL microwave vial waspurged with nitrogen for 5 min. DMF (3 mL) and TMEDA (0.03 mmol; 3.6 mg)were added. The vial was sealed and heated at 140° C. in a microwavereactor for 20 min. The reaction mixture was filtered through celite,washed with EtOAc. Filtrate was concentrated to give a crude productwhich was purified by reverse phase HPLC to give the title compound asan off-white solid (5.7 mg, 9.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ11.33 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 7.75 (td, J=8.3, 6.2 Hz, 1H),7.68 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.54 (t, J=8.9 Hz, 1H), 2.43 (s,3H). LCMS (Method B): RT=4.33 min, m/z 397.1 [M+H⁺].

Example 1532-(2-cyano-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridine-7-carbonitrile

The title compound was obtained from the purification of Example 151 asan off-white solid (9.9 mg, 17% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.83(s, 1H), 8.71 (s, 1H), 8.05-8.00 (m, 1H), 7.92 (dt, J=13.0, 6.5 Hz, 2H),7.70 (s, 1H), 6.54 (s, 1H), 2.42 (s, 3H). LCMS (Method B): RT=3.98 min,m/z 388.1 [M+H⁺].

Example 154(2-(2-chloro-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-7-yl)methanol

Step 1:2-(2-chloro-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridine-7-carbaldehyde

To a solution of2-(2-chloro-6-fluoro-phenyl)-4-[(6-methylpyrimidin-4-yl)amino]thiazolo[5,4-c]pyridine-7-carbonitrile(0.0500 mmol, 61.8 mg) in formic acid (2.25 mL) and water (0.75 mL) wasadded Al—Ni Alloy (130 mg). The mixture was heated at 100° C. for 4hours. The mixture was then cooled to room temperature and filteredthrough celite, washed with 95% EtOH, concentrated via rotavap to give ayellow solid which was used in the next step without purification. LCMS(ESI) m/z 400.1 [M+H⁺].

Step 2:(2-(2-chloro-6-fluorophenyl)-4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-7-yl)methanol

To a solution of2-(2-chloro-6-fluoro-phenyl)-4-[(6-methylpyrimidin-4-yl)amino]thiazolo[5,4-c]pyridine-7-carbaldehyde(0.0500 mmol, 20.0 mg) in MeOH (2 mL) at 0° C. was added NaBH₄ (0.15mmol, 6 mg). The mixture was stirred at room temperature for 2 hours.The reaction was then quenched with water, extracted with EtOAc and thenDCM. The combined organics were dried (Na₂SO₄), filtered andconcentrated to a yellow oil.

The resultant oil was dissolved in THF (2 mL) and MeOH (0.1 mL). Asolution of 1 N NaOH (0.2 mL) was added. The mixture was stirred at roomtemperature for 1 hour. The mixture was then diluted with water,extracted with EtOAc. The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude product was purified by reversephase HPLC to give the title compound as a yellow solid (3.6 mg, 18%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.44 (s, 1H), 8.27 (s,1H), 7.72 (dd, J=14.5, 8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.55-7.45(m, 3H), 5.48 (t, J=5.3 Hz, 1H), 4.98 (d, J=4.8 Hz, 2H), 2.39 (s, 3H).LCMS (Method B): RT^(=3.78) min, m/z 402.1 [M+H⁺].

Example 155 and 156(1S,2S)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamideand(1R,2R)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamide

Step 1. 2-(2,6-Dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine

To a microwave tube was added4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (1.00 g, 2.80mmol), diphenylmethanimine (607 mg., 3.40 mmol), Pd₂(dba)₃ (128 mg,0.140 mmol), BINAP (174 mg, 0.280 mmol), sodium tert-butoxide (403 mg,4.20 mmol), and toluene (15.0 mL). The mixture was degassed withnitrogen for 10 min. The resulting mixture was irradiated in a microwavereactor at 130° C. for 1 hour and then cooled to room temperature. Themixture was filtered through Celite and the filtrate was concentrated.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:10 to 1:2) to give the desired product as asolid (320 mg, 38.7% yield). LCMS (ESI) m/z: 296 [M+H⁺].

Step 2.(1S,2S)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamideand(1R,2R)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamide

To a microwave tube was added2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine (200 mg, 0.680mmol), cis-2-fluorocyclopropanecarboxylic acid (106 mg., 1.02 mmol),HATU (517 mg, 1.36 mmol), DIPEA (263 mg, 1.36 mmol), and DMF (3 mL). Theresulting mixture was irradiated in a microwave reactor at 120° C. for 4hours and then cooled to room temperature. Water (10 mL) was added andthe aqueous layer was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (10 mL) and dried overanhydrous sodium sulfate. After concentration by rotavap, the residuewas purified by silica gel column chromatography eluting with ethylacetate/petroleum ether (1:10 to 1:2) to give a racemic mixture, whichwas purified by chiral HPLC (AD-H, SFC with MeOH as co-solvent) to givetwo desired products as following:

First eluting peak: 23.5 mg, 9.1% yield. >98% ee (3.66 min, AD-H, SFCwith MeOH as co-solvent, 8 min). ¹H NMR (500 MHz, MeOH-d₄): δ 8.44 (d,J=5.5 Hz, 1H), 7.86 (d, J=5 Hz, 1H), 7.62-7.55 (m, 3H), 4.99-4.83 (m,1H), 2.21-2.17 (m, 1H), 1.86-1.78 (m, 1H), 1.28-1.23 (m, 1H). LCMS(Method A): RT=5.58 min, m/z: 382.0 [M+H⁺].

Second eluting peak: 35 mg, 14% yield. >98% ee (5.04 min, AD-H, SFC withMeOH as co-solvent, 8 min.). ¹H NMR (500 MHz, MeOH-d₄): δ 8.45 (d, J=5.5Hz, 1H), 7.87 (d, J=5.5 Hz, 1H), 7.63-7.56 (m, 3H), 5.00-4.84 (m, 1H),2.22-2.16 (m, 1H), 1.87-1.79 (m, 1H), 1.28-1.22 (m, 1H). LCMS (MethodB): RT=5.64 min, m/z: 382.1 [M+H⁺].

Example 157 and 158(1R,2S)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(hydroxymethyl)cyclopropanecarboxamideand(1S,2R)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(hydroxymethyl)cyclopropanecarboxamide

Step 1.3-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione

A solution of 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine (550mg, 1.86 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (835 mg, 7.46mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 2 hours. Thereaction mixture was then cooled to room temperature and concentrated.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:10 to 1:2) to give the desired product as asolid. (570 mg, 78.8% yield). LCMS (ESI) m/z: 390.0 [M+H⁺].

Step 2.(1R,2S)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(hydroxymethyl)cyclopropanecarboxamideand(1S,2R)—N-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-2-(hydroxymethyl)cyclopropanecarboxamide

To a suspension of3-(2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-yl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione(570 mg, 1.46 mmol) in isopropanol (15 mL) and water (3.0 mL) was addedNaBH₄ (278 mg, 7.32 mmol). The reaction mixture was stirred at roomtemperature for 1 hour. The volatile solvent was removed under reducedpressure. The residue was diluted with water, extracted with EtOAc (3×10mL). The combined organics were dried (Na₂SO₄), filtered, andconcentrated. The crude product was purified by column chromatographyeluting with ethyl acetate/petroleum ether (1:5 to 1:2) to give aracemic mixture, which was purified by chiral HPLC (AD-H, SFC with MeOHas co-solvent) to give two desired products as following:

First eluting peak: 27.5 mg, 4.8% yield. >98% ee (3.46 min, AD-H, SFCwith MeOH as co-solvent, 8 mim). ¹H NMR (500 MHz, DMSO-d₆): δ 8.42 (d,J=6.0 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.62-7.56 (m, 3H), 3.86-3.83 (m,1H), 3.74-3.69 (m, 1H), 2.15-2.10 (m, 1H), 1.69-1.66 (m, 1H), 1.18-1.15(m, 2H). LCMS (Method A): RT=4.90 min, m/z: 394.0 [M+H⁺].

Second eluting peak: 23.5 mg, 3.3% yield. >98% ee (5.06 min, AD-H, SFCwith MeOH as co-solvent, 8 mim). ¹H NMR (500 MHz, DMSO-d₆): δ 8.42 (d,J=5.5 Hz, 1H), 7.83 (d, J=5 Hz, 1H), 7.62-7.56 (m, 3H), 3.86-3.83 (m,1H), 3.74-3.69 (m, 1H), 2.15-2.10 (m, 1H), 1.69-1.66 (m, 1H), 1.18-1.15(m, 2H). LCMS (Method A): RT=4.90 min, m/z: 394.0 [M+H⁺].

Example 1592-(4-amino-2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

Step 1: Dimethyl 2-chloro-6-fluoroterephthalate

An autoclave equipped with a stir bar was charged with2,5-dibromo-1-chloro-3-fluorobenzene (5.0 g, 17.3 mmol), triethylamine(12.1 mL, 86.7 mmol), bis(diphenylphosphino)ferrocene)palladium(II)Chloride (0.86 mmol, 708 mg) and methanol (100 mL) was degassed withnitrogen for 10 min. Then the container was sealed and filled with CO to400 psi. The reaction mixture was heated at 100° C. with stirring for 12hours. The reaction mixture was filtered through Celite, washed withMeOH, and the filtrate was concentrated. The crude product was purifiedby silica gel chromatography (0-10% EtOAc/hexane) to afford the titlecompound as a colorless oil which solidified in high vacuum (3.06 g, 71%yield). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.69 (dd, J=9.0, 1.2 Hz,1H), 3.99 (s, 3H), 3.95 (s, 3H). LCMS (APCI+) 247.0[M+H]⁺

Step 2: 3-Chloro-5-fluoro-4-(methoxycarbonyl)benzoic acid

To a solution of dimethyl 2-chloro-6-fluoroterephthalate (6.19 g, 25.1mmol) in tetrahydrofuran (75 mL) was added a solution of 1 N NaOH (27.6mmol, 27.6 mL). The reaction mixture was stirred at room temperature for30 min. After the volatiles were removed under reduced pressure, water(30 mL) was added. The aqueous solution was acidified with 1 N HCl to pH3.0. A white solid precipitated and was collected by filtration, washedwith water and diethyl ether, dried in high vacuum to afford the titlecompound as a white solid (5.54 g, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ7.96 (s, 1H), 7.76 (dd, J=8.8, 1.3 Hz, 1H), 4.01 (s, 3H). LCMS (APCI+)233.0 [M+H]⁺.

Step 3: Methyl 4-(tert-butoxycarbonylamino)-2-chloro-6-fluorobenzoate

To a solution of 3-chloro-5-fluoro-4-methoxycarbonyl-benzoic acid (5.55g, 23.84 mmol) in tert-butanol (48 mL) was added diphenylphosphorylazide (7.22 g, 26.2 mmol) and triethylamine (2.65 g, 26.2mmol). The mixture was heated at 85° C. for 20 hours, then concentratedvia rotavap. The crude product was purified by silica gel chromatography(0-20% EtOAc/hexane) to give the title compound. (6.53 g, 90.2% yield)as a colorless oil. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.32 (dd, J=11.7, 1.7 Hz,1H), 7.28 (s, 1H), 7.05 (s, 1H), 3.95 (s, 3H), 1.54 (s, 9H). LCMS (ESI)m/z 304.0 [M+H⁺].

Step 4: Methyl 4-amino-2-chloro-6-fluorobenzoate

To a solution of methyl4-(tert-butoxycarbonylamino)-2-chloro-6-fluoro-benzoate (6.53 g, 21.5mmol) in dichloromethane (40 mL) was added TFA (9.94 mL). The mixturewas stirred at room temperature for 4 hours. The mixture was thenconcentrated. Water (30 mL) was added to the residue, and pH wasadjusted 10 with 25% NaOH. The resulting suspension was extracted withEtOAc (3×). The combined organics were dried (Na₂SO₄), filtered andconcentrated to give the title compound (4.41 g, quantitative yield) asan off-white solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 6.54 (s, 1H), 6.34 (dd,J=11.6, 2.1 Hz, 1H), 4.19 (s, 2H), 3.90 (s, 3H). LCMS (ESI) m/z 204.0[M+H⁺].

Step 5: Methyl 2-chloro-6-fluoro-4-iodobenzoate

Methyl 4-amino-2-chloro-6-fluoro-benzoate (3.74 g, 18.4 mmol) was addedto conc. HCl (110 mL). The mixture was cooled to 0° C. A solution ofNaNO₂ (2.53 g, 36.7 mmol) in water (7 mL) was added dropwise withvigorous stirring. After stirring at 0° C. for 1.5 hours, a solution ofKI (15.2 g, 91.8 mmol) in water (18 mL)) was added dropwise. The mixturewas warmed up to room temperature and stirred overnight. The mixture wasthen extracted with DCM (3×). The combined organics were washed with 10%Na₂S₂O₃ (50 mL), brine, dried (Na₂SO₄), filtered and concentrated. Thecrude product was purified by silica gel chromatography (0-10%EtOAc/hexane) to give the title compound (4.48 g, 77.6% yield) as alight yellow oil. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.69 (s, 1H), 7.52 (dd,J=8.3, 1.2 Hz, 1H), 3.97 (s, 3H). LCMS (ESI) m/z 314.8 [M+H⁺].

Step 6: 2-Chloro-6-fluoro-4-iodobenzoic acid

To a solution of methyl 2-chloro-6-fluoro-4-iodo-benzoate (4.48 g, 14.2mmol) in pyridine (28 mL) was added LiI (4.0 g, 29.9 mmol). The reactionmixture was heated at 115° C. for 4 hours. The solvent was removed undervacuum. The resultant solid was dissolved in water, and extracted withEtOAc. The aqueous layer was acidified with 1 N HCl to pH=4, extractedwith EtOAc (3×30 mL). The combined organic phases were washed with 10%citric acid (2×30 mL), brine, dried (Na₂SO₄), filtered and concentratedto give the title compound (4.77 g, quantitative yield) as a yellowsolid. ¹H NMR (400 MHz, methanol-d₄) δ 7.73 (s, 1H), 7.62 (dd, J=8.4,1.1 Hz, 1H). LCMS (ESI) m/z 300.8 [M+H⁺].

Step 7:2-Chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-fluoro-4-iodobenzamide

To a 250 ml RB flask was added 2-chloro-6-fluoro-4-iodo-benzoic acid(4.53 g, 15.1 mmol), followed by toluene (30 mL) and thionyl chloride(11 mL). The mixture was heated at 80° C. for 2 hours before beingcooled to room temperature and concentrated to dryness. The crudeproduct was azeotroped from anhydrous toluene twice (10 ml) and directlycarried to the next step.

To a solution of 2-chloro-3-fluoro-pyridin-4-amine (3.31 g, 22.6 mmol)in THF (50 mL) at 0° C. was slowly added LiHMDS in THF (1.0 M, 45 mL).The mixture was warmed to room temperature and allowed to stir for 1hour. It was then cooled to −78° C. A THF solution of2-chloro-6-fluoro-4-iodo-benzoyl chloride (15.1 mmol, 15 mL) was addeddropwise. The mixture was stirred at −78° C. for 1 hour. The reactionwas then quenched with sat. NH₄Cl, extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, concentrated. The crudeproduct was purified by silica gel column chromatography (0-25%EtOAc/hexane) to give the title compound (4.97 g, 76.8% yield) as anoff-white solid. ¹H NMR (400 MHz, methanol-d₄) δ 8.37 (t, J=5.4 Hz, 1H),8.18 (d, J=5.5 Hz, 1H), 7.80 (s, 1H), 7.69 (dd, J=8.2, 1.2 Hz, 1H). LCMS(ESI) m/z 429.0 [M+H⁺].

Step 8:4-Chloro-2-(2-chloro-6-fluoro-4-iodophenyl)thiazolo[5,4-c]pyridine

The solution of2-chloro-N-(2-chloro-3-fluoro-4-pyridyl)-6-fluoro-4-iodo-benzamide (2.4g, 5.59 mmol) in thionyl chloride (40.6 mL) was heated at 90° C. for 5days. The solvent was removed under reduced pressure, azeotroped withtoluene twice to give an off-white solid which was directly used in thenext step.

To the solid from last step was added isopropanol (20 mL), thiourea(1.72 g, 22.4 mmol) and pyridine (1.77 g, 22.4 mmol). The mixture washeated at 85° C. for 4 hours. Triethylamine (2.83 g, 28.0 mmol) was thenadded, and the mixture was heated at 85° C. for additional 4 hours. Themixture was concentrated. The residue was partitioned between DCM andwater. The layers were separated and the aqueous layer was extractedwith DCM two more times. The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude product was purified by silica gelchromatography (0-15% EtOAc/hexane) to give the title compound (1.515 g,63.7% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=5.6Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (s, 1H), 7.59 (dd, J=8.3, 1.1 Hz,1H). LCMS (ESI) m/z 425.0 [M+H⁺].

Step 9: tert-Butyl3-chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorophenylcarbamate

A mixture of4-chloro-2-(2-chloro-6-fluoro-4-iodo-phenyl)thiazolo[5,4-c]pyridine (715mg, 1.682 mmol), tert-butyl carbamate (394 mg, 3.365 mmol), Pd₂(dba)₃(77 mg, 0.084 mmol), and XantPhos (97 mg, 0.168 mmol) in toluene (17 mL)and K₃PO₄ (2.65 mL, 1.27 M) was heated at 90° C. under nitrogen for 20hours. The reaction mixture was diluted with water, extracted with EtOAc(2×). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by silica gel flashchromatography (0-25% EtOAc/hexane) to give the title compound (550 mg,78.9% yield) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d,J=5.6 Hz, 1H), 7.95 (d, J=5.6 Hz, 1H), 7.46-7.33 (m, 2H), 6.70 (s, 1H),1.55 (s, 9H). LCMS (ESI) m/z 414.1 [M+H⁺].

Step 10:2-(4-Amino-2-chloro-6-fluoro-phenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine

A mixture of tert-butylN-[3-chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluoro-phenyl]carbamate(56 mg, 0.135 mmol), 6-methylpyrimidin-4-amine (44 mg, 0.40 mmo),Pd₂(dba)₃ (6.2 mg, 0.00676 mmol), XantPhos (7.8 mg, 0.0135 mmol) andCs₂CO₃ (88 mg, 0.27 mmol) in 1,4-Dioxane (2 mL) was heated at 150° C. ina microwave reactor for 20 min. The mixture was filtered through Celite,washed with EtOAc, concentrated. The crude product was purified byreverse phase HPLC to give the title compound (5.4 mg, 10% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.61 (s, 1H),8.39 (d, J=5.6 Hz, 1H), 7.75 (d, J=5.6 Hz, 1H), 7.58 (s, 1H), 6.66 (s,1H), 6.49 (dd, J=12.7, 2.0 Hz, 1H), 6.34 (s, 2H), 2.38 (s, 3H). LCMS(Method B): RT=3.43 min, m/z 387.0 [M+H⁺].

Additional compounds shown in Table 2 were also made according to theabove procedures.

TABLE 2 LCMS Synth. (ESI) LCMS Ex- Meth- m/z Meth- R_(T) ample StructureName od [M + H⁺] od (min) NMR 160

Cyclopropylmethyl 2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin-4-ylcarbamate 2 394.1 B 6.67 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.78 (br s,1H), 8.43 (d, J = 5.5 Hz, 1H), 7.91 (d, J = 5.5 Hz, 1H), 7.74-7.65 (m,3H), 4.00 (d, J = 7.5 Hz 2H), 1.23-1.17 (m, 1H), 0.56-0.54 (m, 2H),0.34-0.33 (m, 2H). 161

2-(2,6- Dichlorophenyl)-N- (5-methylpyrazin- 2-yl)thiazolo[5,4-c]pyridin-4-amine 2 388.1 B 6.11 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.37 (brs, 1H), 9.10 (s, 1H), 8.36 (d, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.74-7.65(m, 4H), 2.43 (s, 3H). 162

2-(2-Chloro-6- fluorophenyl)-N-(5- methylpyrazin-2- yl)thiazolo[5,4-c]pyridin-4-amine 2 372.0 A 5.74 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.38 (brs, 1H), 9.08 (d, J = 0.5 Hz, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.21 (s,1H), 7.74-7.50 (m, 4H), 2.43 3H). 163

5-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4- ylamino)pyrazine-2-carbonitrile 2 399.1 B 6.49 ¹H-NMR (500 MHz, DMSO-d₆): δ 11.35 (br s,1H), 9.16 (s, 1H), 8.84 (s, 1H), 8.50 (d, J = 3.5 Hz, 1H), 7.92 (s, 1H),7.75-7.67 (m, 3H). 164

(5-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4-ylamino)pyrazin-2- yl)methanol 2 404.0 B 5.06 ¹H-NMR (500 MHz, DMSO-d₆):δ 9.10 (s, 1H), 8.37 (d, J = 3.5 Hz, 1H), 8.34 (s, 1H), 7.74-7.67 (m,4H), 4.57 (s, 2H). 165

2-(2,6- Dichlorophenyl)-N- (6- methylpyrimidin-4- yl)thiazolo[5,4-c]pyridin-4-amine 2 388.0 B 5.71 ¹H-NMR (500 MHz, DMSO-d₆): δ 8.64 (s,1H), 8.46 (d, J = 5.5 Hz, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.75-7.61 (m,4H), 2.40 (s, 3H). 166

Cyclopropylmethyl 2-(2-chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylcarbamate 2 378.0 B 6.42 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.80 (br s,1H), 8.44 (d, J = 5.5 Hz, 1H), 7.91 (d, J = 5.5 Hz, 1H), 7.72-7.50 (m,3H), 4.00 (d, J = 7.5 Hz 2H), 1.23-1.16 (m, 1H), 0.56-0.53 (m, 2H),0.34-0.33 (m, 2H). 167

2-(2,6- Dichlorophenyl)-N- (6- (morpholinomethyl) pyrimidin-4-yl)thiazolo[5,4- c]pyridin-4-amine 2 473.1 B 5. 46 ¹H-NMR (500 MHz,DMSO-d₆): δ 10.71 (br s, 1H), 8.66 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H),7.84-7.65 (m, 5H), 3.64-3.62 (m, 4H), 3.53 (s, 2H), 2.50-2.47 (m, 4H).168

2-(2-Chloro-6- fluorophenyl)-N-(6- (morpholinomethyl) pyrimidin-4-yl)thiazolo[5,4- c]pyridin-4-amine 2 457.1 B 5.22 ¹H-NMR (500 MHz,DMSO-d₆): δ 10.72 (br s, 1H), 8.66 (s, 1H), 8.45 (d, J = 6.0 Hz, 1H),7.85-7.51 (m, 5H), 3.64-3.62 (m, 4H), 3.53 (s, 2H), 2.50-2.47 (m, 4H).169

(R)-1-(6-(2-(2- Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4-yl)ethanol 2 402.0 A 4.89 ¹H-NMR (500 MHz,DMSO-d₆): δ 10.73 (br s, 1H), 8.65 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H),7.86-7.51 (m, 5H), 5.53 (d, J = 5.0 Hz, 1H), 4.60 (t, J = 5.5 Hz, 1H),1.38 (t, J = 6.0 Hz, 3H). 170

(S)-1-(6-(2-(2- Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrimidin- 4-yl)ethanol 2 402.0 A 4.89 ¹H-NMR (500 MHz,DMSO-d₆): δ 10.73 (br s, 1H), 8.65 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H),7.86-7.51 (m, 5H), 5.53 (d, J = 5.0 Hz, 1H), 4.60 (t, J = 5.5 Hz, 1H),1.37 (t, J = 6.0 Hz, 3H). 171

(R)-1-(6-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4-ylamino)pyrimidin- 4-yl)ethanol 2 418.0 A 5.11 ¹H-NMR (500 MHz,DMSO-d₆): δ 10.73 (br s, 1H), 8.65 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H),7.86-7.66 (m, 5H), 5.53 (d, J = 4.5 Hz, 1H), 4.60 (t, J = 5.5 Hz, 1H),1.37 (d, J = 6.5 Hz, 3H). 172

(S)-1-(6-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4-ylamino)pyrimidin- 4-yl)ethanol 2 418.0 A 5.11 ¹H-NMR (500 MHz,DMSO-d₆): δ 10.73 (br s, 1H), 8.65 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H),7.86-7.66 (m, 5H), 5.53 (d, J = 4.5 Hz, 1H), 4.60 (t, J = 5.5 Hz, 1H),1.37 (d, J = 6.5 Hz, 3H). 173

(R)-N-(6-(1- Aminoethyl)pyrimi- din-4-yl)-2-(2,6- dichlorophenyl)thia-zolo[5,4-c]pyridin- 4-amine 2 417.0 A 4.95 ¹H-NMR (500 MHz, DMSO-d₆): δ10.69 (br s, 1H), 8.66 (d, J = 1 Hz, 1H), 8.45 (d, J = 5.0 Hz, 1H),7.84-7.65 (m, 4H), 3.90-3.87 (m, 1H), 1.29 (d, J = 6.5 Hz, 3H). 174

(S)-N-(6-(1- Aminoethyl)pyrimi- din-4-yl)-2-(2,6- dichlorophenyl)thia-zolo[5,4-c]pyridin- 4-amine 2 417.0 A 4.95 ¹H-NMR (500 MHz, DMSO-d₆): δ10.76 (br s, 1H), 8.66 (d, J = 1 Hz, 1H), 8.45 (d, J = 5.0 Hz, 1H),7.84-7.65 (m, 4H), 3.90-3.86 (m, 1H), 1.28 (d, J = 6.5 Hz, 3H). 175

5-(2-(2-Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrazine- 2-carbonitrile 2 383.0 A 5.98 ¹H NMR (500 MHz,DMSO-d₆): δ 9.10 (s, 1H), 8.83 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 7.90(d, J = 5.5 Hz, 1H), 7.75-7.70 (m, 3H). 176

N-(5- (Aminomethyl)pyra- zin-2-yl)-2-(2,6- dichlorophenyl)thia-zolo[5,4-c]pyridin- 4-amine 2 403.0 A 4.96 ¹H NMR (500 MHz, DMSO-d₆): δ9.13 (br s, 1H), 8.39-8.37 (m, 2H), 7.75-7.66 (m, 5H), 3.94 (s, 2H),3.50 (br s, 2H). 177

2-(2,6- Dichlorophenyl)-N- (5- ((methylamino) methyl)pyrazin-2-yl)thiazolo[5,4- c]pyridin-4-amine 2 417.1 B 4.79 ¹H NMR (500 MHz,DMSO-d₆): δ 10.47 (br s, 1H), 9.12 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H),8.31 (s, 1H), 7.75-7.73 (m, 3H), 7.69-7.66 (m, 1H), 3.73 (s, 2H), 2.31(s, 3H). 178

(5-(2-(2-Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylamino)pyrazin-2- yl)methanol 2 388.0 B 4.84 ¹H NMR (500 MHz, DMSO-d₆):δ 10.48 (br s, 1H), 9.10 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H) 8.34 (s,,1H), 7.75-7.69 (m, 2H), 7.62-7.50 (m, 2H), 5.43 (t, J = 6.0 Hz, 1H),4.57 (d, J = 6.0 Hz, 2H). 179

N-(5- (Aminomethyl)pyra- zin-2-yl)-2-(2- chloro-6- fluorophenyl)thiazolo[5,4-c]pyridin-4- amine 2 386.9 B 4.51 ¹H NMR (500 MHz, DMSO-d₆): δ 9.10(m, 1H), 8.36-8.23 (m, 2H), 7.74-7.51 (m, 4H), 4.23 (d, J = 5.5 Hz, 1H),3.82 (s, 2H). 180

2-(2-Chloro-6- fluorophenyl)-N-(5- ((methylamino) methyl)pyrazin-2-yl)thiazolo[5,4- c]pyridin-4-amine 2 401.1 A 5.13 ¹H NMR (500 MHz,DMSO-d₆): δ 10.48 (br s, 1H), 9.11 (s, 1H), 8.37 (d, J = 5.0 Hz, 1H),8.32 (s, 1H), 7.74-7.69 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.53 (t, J =8.5 Hz, 1H), 3.75 (s, 2H), 2.32 (s, 3H). 181

6-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4- ylamino)-Nmethylpyridazine- 3-carboxamide 2 431.0 A 5.40 ¹H NMR (500 MHz,DMSO-d₆): δ 11.06 (s, 1H), 8.92 (d, J = 5.5 Hz, 1H), 8.41 (d, J = 7.0Hz, 1H), 8.18 (d, J = 11.5 Hz, 1H), 8.10 (d, J = 11.5 Hz, 1H), 7.83-7.45(m, 4H), 2.83 (d, J = 6.0 Hz, 3H). 182

Ethyl 2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin- 4-ylcarbamate 2368.0 B 6.16 ¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (br s, 1H), 8.43 (d, J =5.5 Hz, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.74-7.72 (m, 2H), 7.68-7.64 (m,1H), 4.21-4.16 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H). 183

Ethyl 2-(2-chloro- 6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylcarbamate 2 352.0 B 5.89 ¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (br s,1H), 8.44 (d, J = 5.5 Hz, 1H), 7.92 (d, J = 5.5 Hz, 1H), 7.74-7.69 (m,1H), 7.61 (d, J = 8.5 Hz, 1H), 7.54-7.50 (m, 1H), 4.22-4.18 (m, 2H),1.27 (t, J = 7.5 Hz, 3H). 184

Isopropyl 2-(2- chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-ylcarbamate 2 366.0 B 6.34 ¹H NMR (500 MHz, DMSO-d₆): δ 10.67 (s, 1H),8.43 (d, J = 5.5 Hz, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.74-7.69 (m, 1H),7.61 (d, J = 8.5 Hz, 1H), 7.54-7.50 (m, 1H), 4.97-4.91 (m, 1H), 1.29 (d,J = 6.0 Hz, 6H). 185

1-(2-(2-Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- yl)-3-(2-hydroxyethyl)urea 2 367.1 B 4.54 ¹H NMR (500 MHz, DMSO-d₆): δ 9.76 (brs, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.01 (br s, 1H), 7.74-7.68 (m, 2H),7.60 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 4.81 (br s, 1H),3.52-3.48 (m, 2H), 3.28-3.24 (m, 2H). 186

N²-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4- yl)pyrazine-2,5-diamine 2 389.0 B 1.90 ¹H NMR (500 MHz, DMSO-d₆): δ 9.62 (s, 1H), 8.48(d, J = 1.5 Hz, 1H), 8.21 (d, J = 6.0 Hz, 1H), 7.73-7.65 (m, 4H), 7.52(d, J = 5.0 Hz, 1H), 6.14 (s, 2H). 187

N²-(2-(2-Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-yl)pyrazine-2,5- diamine 2 373.1 B 4.78 ¹H NMR (500 MHz, DMSO-d₆): δ9.63 (br s, 1H), 8.47 (d, J = 1.0 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H),7.71-7.70 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.53-7.50(m, 2H), 6.14 (s,2H). 188

2-Cyano-N-(2-(2,6- dichlorophenyl)thia- zolo[5,4-c]pyridin-4-yl)acetamide 2 363.0 B 5.19 ¹H NMR (500 MHz, DMSO-d₆): δ 9.63 (br s,1H), 8.49 (d, J = 6.0 Hz, 1H), 7.99 (d, J = 5.5 Hz, 1H), 7.75-7.66 (m,3H), 4.12 (s, 2H). 189

N-(2-(2-Chloro-6- fluorophenyl)thiazolo [5,4-c]pyridin-4- yl)-2-cyanoacetamide 2 347.1 B 4.94 ¹H NMR (500 MHz, DMSO-d₆): δ 11.48 (br s,1H), 8.49 (d, J = 5.5 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.73-7.50 (m,3H), 4.12 (s, 2H). 190

N-(6- Cyclopropylpyrimi- din-4-yl)-2-(2,6- dichlorophenyl)thia-zolo[5,4-c]pyridin- 4-amine 2 414.1 B 6.64 ¹H NMR (500 MHz, DMSO-d₆): δ8.56 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 7.83-7.65 (m, 5H), 2.03 (t, J =6.5 Hz, 1H), 1.00 (d, J = 6.5 Hz, 4H). 191

2-(2,6- Dichlorophenyl)-N- (5-ethylpyrazin-2- yl)thiazolo[5,4-c]pyridin-4-amine 2 402.1 B 6.64 ¹H NMR (500 MHz, DMSO-d₆): δ 10.40 (s,1H), 9.10 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.74-7.66 (m,4H), 2.76-2.71 (m, 2H), 1.24 (t, J = 8.0 Hz, 3H). 192

4-[(5-{[2-(2- Chloro-6- fluorophenyl)- [1,3]thiazolo[5,4- c]pyridin-4-yl]amino}pyrazin- 2-yl)methyl]- 1λ⁶,4- thiomorpholine- 1,1-dione 2 504.9B 5.20 ¹H-NMR (500 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.38-8.36 (m, 2H),7.76-7.53 (m, 4H), 6.31(s, 1H) 3.79 (s, 2H), 3.13-3.12 (m, 4H),2.97-2.95 (m, 4H). 193

2-(2,6- Dichlorophenyl)-N- (5-methylpyridin-2- yl)thiazolo[5,4-c]pyridin-4-amine 2 388.7 B 6.96 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.08 (brs, 1H), 8.31 (d, J = 5.0 Hz, 1H), 8.10 (s, 1H), 7.74-7.59 (m, 6H), 2.24(s, 3H). 194

2-(2,6- Dichlorophenyl)-N- (5-ethylpyridin-2- yl)thiazolo[5,4-c]pyridin-4-amine 2 401.7 B 7.40 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.10 (brs, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.11 (s, 1H), 7.73-7.60 (m, 6H),2.58-2.54 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H). 195

2-(2-Chloro-6- fluorophenyl)-N-(5- ethylpyrazin-2- yl)thiazolo[5,4-c]pyridin-4-amine 2 386.1 B 6.42 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.40 (brs, 1H), 9.09 (s, 1H), 8.45- 8.35 (m, 1H), 8.22 (s, 1H), 7.74-7.50 (m,4H), 2.76-2.63 (m, 2H), 1.24 (t, J = 7.5 Hz, 3H). 196

2-(2-Chloro-6- fluorophenyl)-N-(5- (morpholinomethyl) pyrazin-2-yl)thiazolo[5,4- c]pyridin-4-amine 2 457.1 A 5.43 ¹H-NMR (500 MHz,DMSO-d₆): δ 9.09 (s, 1H), 8.25 (br, 2H), 7.71- 7.50 (m, 4H), 3.60-3.53(m, 6H), 2.45-2.36 (m, 4H). 197

N-(6-(1- Aminoethyl)pyrimi- din-4-yl)-2-(2- chloro-6-fluorophenyl)thiazolo [5,4-c]pyridin-4- amine 2 401.1 B 4.63 ¹H-NMR (500MHz, MeOD-d₄): δ 8.70 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 7.87 (s, 1H),7.81 (d, J = 5.5 Hz, 1H), 7.68- 7.63 (m, 1H), 7.53 (d, J = 8 Hz, 1H),7.39-7.36 (m, 1H), 4.08-4.03 (m, 1H), 1.47 (d, J = 6.5 Hz, 3H). 198

3-Fluoro-2-(4-(6- methylpyrimidin-4- ylamino)thiazolo[5,4- c]pyridin-2-yl)benzonitrile 2 363.2 B 4.88 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.70 (br s,1H), 8.63 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 7.0 Hz, 1H)7.94-7.83 (m, 3H), 7.60 (s, 1H), 2.40 (s, 3 H). 199

2-(4-(6- Aminopyrimidin-4- ylamino)thiazolo[5,4- c]pyridin-2-yl)-3-fluorobenzonitrile 2 364.1 B 4.24 ¹H-NMR (500 MHz, DMSO-d₆): δ 10.15 (brs, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.12 (s, 1H), 8.02-7.87 (m, 3H), 7.75(d, J = 5.5 Hz 1H), 6.82 (s, 1H), 6.67 (br s, 2H). 200

3-Fluoro-2-(4-(6- (hydroxymethyl) pyrimidin-4- ylamino)thiazolo[5,4-c]pyridin-2- yl)benzonitrile 2 379.1 B 4.22 ¹H-NMR (500 MHz, DMSO-d₆): δ8.63 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 7.0 Hz, 1H),7.93-7.86 (m, 3H), 7.77 (s, 1H), 5.58 (m, 1H), 4.49 (d, J = 5.5 Hz, 2H).201

3-Fluoro-2-(4-(6- (methylamino) pyrimidin-4- ylamino)thiazolo[5,4-c]pyridin-2- yl)benzonitrile 2 378.1 B 4.85 ¹H-NMR (500 MHz, DMSO-d₆): δ10.15 (br s, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J =7.5 Hz, 1H), 7.93-7.88 (m, 2H), 7.75 (d, J = 6.0 Hz 1H), 7.19 (br s,1H), 6.84 (br s, 1H), 2.80 (d, J = 4.5 Hz, 3H) 202

N-(2-(2-Cyano-6- fluorophenyl)thiazolo [5,4-c]pyridin-4-yl)cyclopropane- carboxamide 2 339.1 B 5.13 ¹H-NMR (500 MHz, DMSO-d₆): δ11.45 (br s 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.01-7.87 (m, 4H), 2.11-2.08(m, 1H), 0.93-0.91(m, 4H). 203

(1S,2R)-N-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4-yl)-2-fluorocyclopropane- carboxamide 2 382.0 B 6.08 ¹H-NMR (500 MHz,MeOH-d₄): δ 8.34 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 6.0 Hz, 1H),7.52-7.46 (m, 3H), 4.87-4.72 (m, 1H), 2.40-2.33 (m, 1H), 1.49-1.45 (m,1H), 1.33-1.29 (m, 1H). 204

(1R,2S)-N-(2-(2,6- Dichlorophenyl) thiazolo[5,4- c]pyridin-4-yl)-2-fluorocyclopropane- carboxamide 2 382.0 B 6.08 ¹H-NMR (500 MHz,MeOH-d₄): δ 8.46 (d, J = 6.0 Hz, 1H), 7.87 (d, J = 5.5 Hz, 1H),7.64-7.57 (m, 3H), 4.99-4.84 (m, 1H), 2.50-2.45 (m, 1H), 1.61-1.57 (m,1H), 1.45-1.41 (m, 1H). 205

N-[2-(4- Aminomethyl-2,6- dichlorophenyl)- thiazolo[5,4-c]pyridin-4-yl]-2- methylpyrimidine- 4,6-diamine diformate salt 2 432 C2.04 ¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (d, J = 5.6 Hz, 1H), 8.24 (s,2H), 7.70 (t, J = 2.8 Hz, 3H), 6.57-6.48 (m, 3H), 3.87 (br s, 2H), 2.24(s, 3H). 206

Cyclopropane- carboxylic acid [2-(4- amino-2,6- dichlorophenyl)-thiazolo[5,4- c]pyridin-4-yl]- amide hydrochloride salt 2 379 C 3.90 ¹HNMR (400 MHz, DMSO-d₆): δ 11.41 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.87(d, J = 5.6 Hz, 1H), 6.76 (s, 2H), 2.12- 2.02 (m, 1H), 0.95-0.84 (m,4H). 207

{6-[2-(2-Chloro-6- fluorophenyl)-7- fluorothiazolo[5,4- c]pyridin-4-ylamino]- pyrimidin-4-yl}- methanol 2 406 C 3.51 ¹H NMR (400 MHz,DMSO-d₆): δ 10.75 (br s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.49 (d, J = 1.9Hz, 1H), 7.77-7.69 (m, 1H), 7.66-7.49 (m, 3H), 5.56 (t, J = 5.8 Hz, 1H),4.47 (d, J = 5.7 Hz, 2H). 208

N-[2-(2-Chloro-6- fluorophenyl)-7- fluorothiazolo[5,4-c]pyridin-4-yl]-2- methylpyrimidine- 4,6-diamine hydrochloride salt 2405 C 3.26 ¹H NMR (400 MHz, DMSO-d₆): δ 11.34 (s, 1H), 8.52 (d, J = 1.8Hz, 1H), 7.79-7.70 (m, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 8.9Hz, 1H), 7.02 (s, 1H), 2.47 (s, 3H). 209

N-[2-(2,6- Dichlorophenyl)-7- fluorothiazolo[5,4- c]pyridin-4-yl]-pyrimidine-4,6- diamine hydrochloride salt 2 407 C 3.31 ¹H NMR (400 MHz,DMSO-d₆): δ 11.67 (br s, 1H), 8.53-8.47 (m, 2H), 7.79-7.70 (m, 3H), 7.04(s, 1H). 210

{6-[2-(2,6- Dichlorophenyl)-7- fluorothiazolo[5,4- c]pyridin-4-ylamino]- pyrimidin-4-yl}- methanol 2 422 C 3.68 ¹H NMR (400 MHz,DMSO-d₆): δ 10.76 (s, 1H), 8.61 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 7.78-7.73 (m, 2H), 7.72-7.65 (m, 1H), 7.60 (s, 1H), 5.56 (t, J = 5.7 Hz, 1H),4.48 (d, J = 5.7 Hz, 2H). 211

1-[2-(2,6- Dichlorophenyl)-7- fluorothiazolo[5,4- c]pyridin-4-yl]-3-methyl-urea 2 371 C 4.43 ¹H NMR (400 MHz, DMSO-d₆): δ 9.77 (s, 1H), 8.34(d, J = 1.9 Hz, 1H), 7.76-7.72 (m, 2H), 7.70-7.65 (m, 1H), 7.31- 7.24(m, 1H), 2.73 (d, J = 4.6 Hz, 3H). 212

N-[2-(2,6- Dichlorophenyl)-7- fluorothiazolo[5,4- c]pyridin-4-yl]-2-methylpyrimidine- 4,6-diamine hydrochloride salt 2 421 C 3.37 ¹H NMR(400 MHz, DMSO-d₆): δ 11.34 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.77-7.65(m, 3H), 6.99 (s, 1H), 2.44 (s, 3H). 213

Cyclopropane- carboxylic acid [2- (2,6- dichloro-4-cyano- phenyl)-7-fluorothiazolo[5,4- c]pyridin-4-yl]- amide 2 407 C 4.83 ¹H NMR (400 MHz,DMSO-d₆): δ 11.50 (s, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.38 (s, 2H), 2.10-2.02 (m, 1H), 0.95-0.83 (m, 4H). 214

3,5-Dichloro-4-[7- fluoro-4-(6- hydroxymethyl- pyrimidin-4-ylamino)-thiazolo[5,4- c]pyridin-2-yl]- benzonitrile 2 447 C 3.67 ¹H NMR (400MHz, DMSO-d₆): δ 10.80 (s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.51 (d, J =1.7 Hz, 1H), 8.40 (s, 2H), 7.58 (s, 1H), 5.57 (t, J = 5.7 Hz, 1H), 4.48(d, J = 5.7 Hz, 2H). 215

4-[4-(6- Aminopyrimidin-4- ylamino)-7- fluorothiazolo[5,4-c]pyridin-2-yl]-3,5- dichlorobenzonitrile 2 432 C 3.28 ¹H NMR (400 MHz,DMSO-d₆): δ 10.19 (s, 1H), 8.40-8.37 (m, 3H), 8.10 (d, J = 1.0 Hz, 1H),6.66 (br s, 2H), 6.55 (d, J = 1.1 Hz, 1H). 216

3-Chloro-2-[4-(6- methylpyrimidin-4- ylamino)- thiazolo[5,4-c]pyridin-2- yl]benzonitrile 2 379 C 3.08 ¹H NMR (400 MHz, DMSO-d₆): δ10.71 (br s, 1H), 8.64 (d, J = 1.2 Hz, 1H), 8.48 (d, J = 5.6 Hz, 1H),8.16-8.05 (m, 2H), 7.89-7.81 (m, 2H), 7.58 (s, 1H), 2.40 (s, 3H). 217

Cyclopropane- carboxylic acid [2-(2- chloro-6- cyanophenyl)-thiazolo[5,4- c]pyridin-4-yl]- amide 2 355 C 4.18 ¹H NMR (400 MHz,DMSO-d₆): δ 11.47 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.13-8.05 (m, 2H),7.96 (d, J = 5.5 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 2.13-2.05 (m, 1H),0.95- 0.86 (m, 4H). 218

2-[4-(6- Aminopyrimidin-4- ylamino)-7- fluorothiazolo[5,4-c]pyridin-2-yl]-3- chlorobenzonitrile hydrochloride salt 2 398 C 3.01 ¹HNMR (400 MHz, DMSO-d₆): δ 11.71 (br s, 1H), 8.55-8.50 (m, 2H), 8.18-8.09(m, 2H), 7.91- 7.86 (m 1H), 7.05 (br s, 1H). 219

2-[4-(6-Amino-2- methyl-pyrimidin- 4-ylamino)-7- fluorothiazolo[5,4-c]pyridin-2-yl]-3- chlorobenzonitrile hydrochloride salt 2 412 C 3.07 ¹HNMR (400 MHz, DMSO-d₆): δ 11.37 (br s, 1H), 8.56 (d, J = 2.0 Hz, 1H),8.17-8.11 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 6.98 (br s, 1H), 3.81 (brs, 3H), 2.47 (s, 3H). 220

Cyclopropane- carboxylic acid [2-(2- chloro-6- cyanophenyl)-7-fluorothia- zolo[5,4-c]pyridin- 4-yl]-amide 2 373 C 4.43 ¹H NMR (400MHz, CDCl₃): δ 8.45 (br s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.79-7.74 (m,2H), 7.58 (t, J = 8.0 Hz, 1H), 1.70- 1.61 (m, 1H), 1.19-1.14 (m, 2H),1.02-0.96 (m, 2H). 221

2-[4-(6- Aminopyrimidin-4- ylamino)-7- fluorothiazolo[5,4-c]pyridin-2-yl]-3- fluorobenzonitrile hydrochloride salt 2 382 C 2.91 ¹HNMR (400 MHz, DMSO-d₆): δ 11.55 (br s, 1H), 8.55-8.48 (m, 2H), 8.08-8.03(m, 1H), 8.01- 7.89 (m, 2H), 7.01 (br s, 1H). 222

3-Fluoro-2-[7- fluoro-4-(6- hydroxy- methylpyrimidin-4- ylamino)thiazolo[5,4-c]pyridin-2-yl]- benzonitrile hydrochloride salt 2 397 C 3.10 ¹HNMR (400 MHz, DMSO-d₆): δ 11.72 (br s, 1H), 8.87 (s, 1H), 8.61 (d, J =2.0 Hz, 1H), 8.07- 8.03 (m, 1H), 7.98-7.88 (m, 2H), 7.71 (s, 1H), 4.61(s, 2H). 223

4-(6- aminopyrimidin-4- ylamino)-2-(2- chloro-6- fluorophenyl)thiazolo[5,4-c]pyridine-7- carbonitrile 2 398.1 B 4.17 ¹H NMR (400 MHz, DMSO-d₆)δ 8.78 (s, 1H), 8.19 (s, 1H), 7.78-7.68 (m, 1H), 7.62 (d, J = 8.1 Hz,1H), 7.53 (t, J = 8.9 Hz, 1H), 6.82 (s, 2H), 6.75 (s, 1H), 6.54 (s, 1H).224

4-(6- aminopyrimidin-4- ylamino)-2-(2- cyano-6- fluorophenyl)thiazolo[5,4-c]pyridine-7- carbonitrile 2 389.1 B 3.93 ¹H NMR (400 MHz, DMSO-d₆)δ 10.85 (s, 1H), 8.81 (s, 1H), 8.20 (s, 1H), 8.02 (d, J = 6.5 Hz, 1H),7.91 (t, J = 6.5 Hz, 2H), 6.87 (s, 2H), 6.80 (s, 1H). 225

5-chloro-4-(4-(2,6- dimethylpyrimidin- 4- ylamino)thiazolo[5,4-c]pyridin-2- yl)isophthalonitrile 2 418.1 B 3.72 ¹H NMR (400 MHz,DMSO-d₆) δ 10.65 (s, 1H), 8.73 (d, J = 7.8 Hz, 2H), 8.47 (d, J = 5.6 Hz,1H), 7.86 (d, J = 5.6 Hz, 1H), 7.21 (s, 1H), 2.45 (s, 3H), 2.34 (s, 3H).226

4-(4-(6- aminopyrimidin-4- ylamino)thiazolo[5,4- c]pyridin-2-yl)-5-chloroisophthalo- nitrile 2 405. 1 B 3.69 ¹H NMR (500 MHz, DMSO-d₆) δ10.23 (s, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 8.40(d, J = 5.6 Hz, 1H), 8.12 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 6.75 (s,1H), 6.68 (s, 2H). 227

2-(4-(2,6- dimethylpyrimidin- 4- ylamino)thiazolo[5,4- c]pyridin-2-yl)benzene-1,3,5- tricarbonitrile 2 409.1 B 3.51 ¹H NMR (400 MHz,DMSO-d₆) δ 10.74 (s, 1H), 9.06 (s, 2H), 8.49 (d, J = 5.6 Hz, 1H), 7.90(d, J = 5.6 Hz, 1H), 7.20 (s, 1H), 2.49 (s, 3H), 2.35 (s, 3H). 228

2-[4-(2-Amino-6- methylpyrimidin-4- ylamino)-7-fluoro- thiazolo[5,4-c]pyridin-2-yl]-3- chlorobenzonitrile hydrochloride salt 2 412 C 2.99 ¹HNMR (400 MHz, DMSO-d₆): δ 11.59 (br s, 1H), 8.64 (d, J = 1.7 Hz, 1H),8.17-8.15 (m, 1H), 8.13-8.10 (m, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.81 (brs, 3H), 6.53 (br s, 1H), 2.35 (s, 3H). 229

3-Chloro-2-[7- fluoro-4-(2- hydroxymethyl-6- methylpyrimidin-4-ylamino)- thiazolo[5,4- c]pyridin-2-yl]- benzonitrile 2 427 C 3.07 ¹HNMR (400 MHz, DMSO-d₆): δ 10.75 (br s, 1H), 8.51 (d, J = 1.8 Hz, 1H),8.16-8.08 (m, 2H), 7.87 (t, J = 8.0 Hz, 1H), 7.22 (s, 1H), 4.96 (t, J =6.1 Hz, 1H), 4.48 (d, J = 6.1 Hz, 2H), 2.28 (s, 3H). 230

2-[4-(6-Amino-2- methylpyrimidin-4- ylamino)-7- fluorothiazolo[5,4-c]pyridin-2-yl]-3- fluorobenzonitrile 2 396 C 2.97 ¹H NMR (400 MHz,DMSO-d₆): δ 10.12 (br s, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.03-8.00 (m,1H), 7.96-7.85 (m, 2H), 6.56 (br s, 1H), 6.29 (s, 1H), 2.39 (s, 3H).

Example 231

3-Chloro-2-[7-fluoro-4-(6-hydroxymethyl-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrilehydrochloride Step 1.(2-Methyl-6-vinyl-aminopyrimidin-4-yl)-bis-carbamic acid tert-butylester

To a solution of (2-methyl-6-chloro-aminopyrimidin-4-yl)-bis-carbamicacid tert-butyl ester (1.50 g, 4.4 mmol), potassium vinyltrifluoroborate(884 mg, 6.6 mmol) and triethylamine (3.3 mL, 22 mmol) in nPrOH (40 mL)was added Pd(dppf)Cl₂ (180 mg, 0.22 mmol). The reaction mixture wasdegassed with nitrogen and then heated at 100° C. for 30 minutes in asealed vial. The resulting mixture was allowed to cool and was thenpartitioned between EtOAc and saturated sodium bicarbonate. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentratedin vacuo. The resultant residue was purified by column chromatography onsilica gel eluting with 10% EtOAc in cyclohexane to afford the titlecompound as an oil (1.99 g, 93%). ¹H NMR (400 MHz, CDCl₃): δ 7.45 (s,1H), 6.70 (dd, J=17.3, 1.3 Hz, 1H), 6.42 (dd, J=17.3, 10.7 Hz, 1H), 5.64(dd, J=10.7, 1.3 Hz, 1H), 2.61 (s, 3H), 1.54 (s, 9H).

Step 2. (6-Hydroxymethyl-2-methyl-aminopyrimidin-4-yl)-bis-carbamic acidtert-butyl ester

Ozone was bubbled through a solution of(2-methyl-6-vinyl-aminopyrimidin-4-yl)-bis-carbamic acid tert-butylester (1.98 g, 5.9 mmol), in DCM (50 mL) and MeOH (12 mL), at −78° C.for 60 minutes (until a permanent blue colour resulted). The flow ofOzone was stopped and then sodium borohydride (448 mg, 11.8 mmol) wasadded at −78° C. The reaction mixture was allowed to stir at −78° C. for10 minutes and was then allowed to warm to room temperature and furtherstirred for 60 minutes. The resulting mixture was then partitionedbetween DCM and water. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The resultant residue waspurified by column chromatography on silica gel eluting with 40-60%EtOAc in cyclohexane to afford the title compound as an oil (1.69 g,84%). LCMS (Method E): RT=3.19 min, m/z: 340 [M+H⁺].

Step 3. (6-Amino-2-methylpyrimidin-4-yl)-methanol

TFA (5 mL) was added to a solution of(6-hydroxymethyl-2-methyl-aminopyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (1.68 g, 5.0 mmol), in DCM (20 mL) and the reactionmixture was stirred at room temperature for 16 hours. The resultingmixture was concentrated in vacuo. The crude residue was dissolved inmethanol and loaded onto an Isolute® SCX-2 cartridge which was washedwith MeOH and the product was then eluted with 2M ammonia in MeOH. Thecombined elution fractions were concentrated in vacuo and the resultantresidue was triturated with diethylether to afford the title compound asa pale pink solid (540 mg, 78%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.64 (brs, 2H), 6.34 (s, 1H), 5.26 (t, J=5.9 Hz, 1H), 4.25 (d, J=5.9 Hz, 2H),2.25 (s, 3H).

Step 4.3-Chloro-2-[7-fluoro-4-(6-hydroxymethyl-2-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrilehydrochloride

To a mixture of2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile(150 mg, 0.41 mmol), (6-amino-2-methylpyrimidin-4-yl)-methanol (56 mg,0.41 mmol), XantPhos (24 mg, 0.042 mmol) and Cs₂CO₃ (345 mg, 1.05 mmol)in 1,4-dioxane (2.5 mL) was added Pd₂(dba)₃ (20 mg, 0.022 mmol), and thereaction mixture was heated under argon at 80° C. for 24 hours. Theresultant mixture was allowed to cool, diluted with water and extractedwith ethyl acetate, then further extracted with 10% methanol in DCM(×5). The resultant insoluble material was filtered off, trituratedtwice with methanol and dried (50° C. under vacuum) to give the freebase of the title compound as a solid (77 mg). The previously combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated invacuo. The resulting residue was purified by chromatography on silica(0-100% ethyl acetate in cyclohexane) to give a further crop of the freebase of the title compound [(30 mg), total yield 107 mg, 61%]. Thecombined batches of free base were suspended in 2-propanol (2 mL), and asolution of hydrogen chloride in 1,4-dioxane (4 N, 2 mL) was added. Themixture was stirred for 1 hour, then the solvent was removed underreduced pressure, and the resultant residue was triturated withdiethylether and dried (50° C. under vacuum) to give the title compoundas an off-white solid (104 mg, 55%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.76(br s, 1H), 8.63 (s, 1H), 8.17-8.09 (m, 2H), 7.88 (t, J=8.1 Hz, 1H),7.44 (br s, 1H), 4.58 (s, 2H), 2.57 (s, 3H). LCMS (Method C): RT=3.07,m/z: 427 [M+H⁺].

Example 232

{6-[2-(4-Amino-2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-methanoldihydrochloride salt Step 1.2,6-Dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzamide

A suspension of 2,6-dichloro-4-iodobenzoyl chloride (24.2 g, 72.1 mmol)in THF (25 mL), was added drop-wise over 10 minutes, to a solution of3,5-difluoropyridin-4-ylamine (10.37 g, 79.7 mmol) in pyridine (100 mL)at a temperature of between 3 and 5° C., under nitrogen. The reactionmixture was allowed to warm to room temperature over 1 hour and thenstirred overnight. The volatiles were removed under reduced pressure andthe resultant residue was treated with HCl (1 N, 90 mL). The resultantsuspension was stirred at room temperature for 45 minutes and theprecipitate obtained was collected by filtration, washing with waterbefore drying. The resultant solid obtained was suspended in 1N NaOH(124 mL) and MeOH (124 mL), and heated at 65° C. for 5 hours then slowlycooled to room temperature. Further MeOH (50 mL) and dioxane (100 mL)were added and the reaction mixture was heated at 75° C. overnight. Theresultant mixture was cooled to room temperature and the organicsolvents removed under reduced pressure. The pH of the aqueous mixturewas adjusted to 4-5 by drop-wise addition of 12 N HCl, controlling theexotherm by the use of an ice-bath. The residue was left standing atroom temperature for 18 hours and then the resultant solid was collectedby filtration, washing with water and dried under vacuum to afford thetitle compound as an off-white solid (21.3 g, 83% yield). LCMS (MethodD): RT=3.46 min, m/z: 429 [M+H⁺].

Step 2. 2,6-Dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzimidoylchloride

A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzamide(21.3 g, 49.7 mmol) in thionyl chloride (118 mL) was heated under refluxfor 20 hours under a nitrogen atmosphere.

After cooling to room temperature, the volatiles were removed underreduced pressure and the resultant residue was azeotroped with toluene(×3) and dried under vacuum to afford the title compound as a brownsolid (22.4 g, quantitative). LCMS (Method E): RT=4.69 min, m/z: 448[M+H⁺].

Step 3. 2-(2,6-Dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine

A suspension of2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzimidoyl chloride(8.8 g, 19.7 mmol), thiourea (6.0 g, 78.8 mol) and pyridine (5.4 mL,66.9 mmol) in isopropanol (80 mL), under a nitrogen atmosphere, washeated under reflux for 6 hours. After this time, the reaction mixturewas cooled to 70° C. and Et₃N (16.4 mL, 118.1 mmol) was added over 5minutes and then the resultant mixture was heated under reflux for afurther 18 hours. Upon cooling to room temperature, the precipitateobtained was collected by filtration and the filtrate was thenpartitioned between water and EtOAc. The aqueous phase was furtherextracted with EtOAc (×2) and the combined organic layers were dried(MgSO₄), filtered and concentrated to dryness to afford the titlecompound as an off-white solid (5.5 g, 66% yield). LCMS (Method D):RT=4.22 min, m/z: 426 [M+H⁺].

Step 4.2-(2,6-Dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine-5-oxide

To a solution of2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine (5.3 g,12.6 mmol) in DCM (100 mL) under a nitrogen atmosphere was addedmethyltrioxorhenium(VII) (313 mg, 1.3 mmol) followed by 30% aqueoushydrogen peroxide (2.6 mL, 25.1 mmol). The reaction mixture was stirredat room temperature for 48 hours with a further two additions ofmethyltrioxorhenium(VII) (313 mg, 1.3 mmol) and 30% aqueous hydrogenperoxide (2.6 mL, 25.1 mmol) added over this period. The precipitateobtained was collected by filtration and the filtrate was partitionedbetween water. The aqueous layer was extracted with DCM (×2). Thecombined organic phases were washed with a saturated solution of NaHCO₃,dried (MgSO₄) and concentrated under reduced pressure. The resultantresidue was combined with the previously filtered solid and was purifiedby column chromatography on silica gel eluting with 0-90% EtOAc inpetroleum ether (40-60° C.), followed by 0-10% MeOH in DCM to afford thetitle compound as a white solid (2.5 g, 45% yield). LCMS (Method D):RT=3.36 min, m/z: 441 [M+H⁺].

Step 5.4-Chloro-2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine

To a suspension of2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine-5-oxide(2.8 g, 6.4 mmol) in 1,2-dichloroethane (80 mL) was added phosphorusoxychloride (1.8 mL, 19.1 mmol). The reaction mixture was heated underreflux for 16 hours. Upon cooling, the resultant mixture was treatedcautiously with aqueous sodium bicarbonate to achieve pH 6-7, and thenextracted with dichloromethane (×2). The combined organic extracts weredried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica geleluting with 0-50% diethyl ether in petroleum ether to afford the titlecompound as a white solid (1.0 g, 34% yield). ¹H NMR (400 MHz, CDCl₃): δ8.35 (d, J=1.5 Hz, 1H), 7.82 (s, 2H).

Step 6.[3,5-Dichloro-4-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)phenyl]-carbamicacid tert-butyl ester

To4-chloro-2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine(579 mg, 1.3 mmol), in toluene (12 mL) and water (2 mL), was addedtert-butyl carbamate (221 mg, 1.9 mmol), XantPhos (72.9 g, 0.13 mmol)and K₃PO₄ (534 mg, 0.34 mmol). The resulting mixture was degassed withargon for 10 minutes, Pd₂(dba)₃ (57.7 mg, 0.063 mmol) was added and thereaction mixture was heated at 100° C. for 18 hours in a sealed vial.After cooling to room temperature, the reaction mixture was filteredthrough Celite® washing with EtOAc (5 mL). The filtrate was partitionedbetween water and the organic layer separated. The aqueous phase wasfurther extracted with EtOAc (×2). The combined organic layers weredried (MgSO₄), filtered concentrated under reduced pressure. Theresultant residue was purified by column chromatography on silica geleluting with 0-100% DCM in cyclohexane to afford the title compound as awhite solid (303 mg, 54% yield). LCMS (Method D): RT=4.86 min, m/z:448.0 [M+H⁺].

Step 7.{3,5-Dichloro-4-[7-fluoro-4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]phenyl}-carbamicacid tert-butyl ester

To a solution of[3,5-dichloro-4-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)phenyl]-carbamicacid tert-butyl ester (150 mg, 0.33 mmol) in dioxane (5 mL), was added(6-aminopyrimidin-4-yl)methanol (45 mg, 0.36 mmol), XantPhos (19.4 mg,0.033 mmol) and Cs₂CO₃ (218.3 mg, 0.67 mmol).

The resultant mixture was degassed with argon for 10 minutes beforePd₂(dba)₃ (57.7 mg, 0.063 mmol) was added and the reaction mixture washeated at 100° C. for 18 hours in a sealed vial. After cooling to roomtemperature, the reaction mixture was filtered through Celite® washingwith EtOAc (5 mL). The resultant residue was purified by columnchromatography on silica gel eluting with 0-80% EtOAc in cyclohexane toafford the title compound as a white foam (102 mg, 58%). LCMS (MethodD): RT=3.35 min, m/z: 538 [M+H⁺].

Step 8.{6-[2-(4-Amino-2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl}-methanoldihydrochloride salt

A mixture of{3,5-dichloro-4-[7-fluoro-4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]phenyl}-carbamicacid tert-butyl ester (102 mg, 0.19 mmol) in HCl (4 N in dioxane, 3 mL)under a nitrogen atmosphere was heated at 50° C. for 5 hours. Aftercooling to room temperature, the precipitate was collected by filtrationand then purified by column chromatography on silica gel eluting with0-5% MeOH in EtOAc. To the resultant solid obtained was added DCM (1 mL)followed by HCl (4 N in dioxane, 1 mL) and the resulting mixture wasstirred at room temperature for 1 hour and then concentrated underreduced pressure to afford the title compound as an off white solid (50mg, 91% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 11.75 (br s, 1H), 8.89 (s,1H), 8.57 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 6.78 (s, 2H), 4.61 (s, 2H).LCMS (Method C): RT=3.11 min, m/z: 437 [M+H⁺].

Example 233

4-[4-(6-Methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-3,5-dichlorobenzamidinebis formate salt

To a solution of3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrile(54 mg, 0.12 mmol) in MeOH (3 mL) was added a solution of sodiummethoxide in methanol (0.054 mL, 0.24 mmol) and the reaction mixture wasstirred at room temperature for 48 hours. After this time, an additionalportion of sodium methoxide in methanol (0.0082 mL, 0.14 mmol) wasadded, stirred for 1 hour and then ammonium chloride (7.0 mg, 7.1 mmol)was added and the resultant mixture was heated at reflux overnight.After cooling to room temperature, additional ammonium chloride (11.4mg, 0.21 mmol) was added and heated at reflux for a further 5 hours. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The resultant residue was purified by reverse phaseHPLC (Phenomenex Gemini 5 μm C18 on a 25 minute gradient 5-50%, 0.1%HCO₂H in CH₃CN/H₂O) to afford the title compound (5.6 mg, 10% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (br s, 1H), 9.60 (s,2H), 9.34 (s, 2H), 8.61 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.14 (s, 2H),7.82 (d, J=5.3 Hz, 1H), 7.54 (s, 1H), 2.41 (s, 3H). LCMS (Method C):RT=2.06 min, m/z: 412 [M+H⁺].

Example 234

3-Chloro-5-fluoro-2-[4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrilehydrochloride Step 1. 2-Amino-3-chloro-5-fluorobenzonitrile

To a solution of 2-amino-5-fluorobenzonitrile (9.90 g, 72.8 mmol) inacetonitrile (200 mL) was added N-chlorosuccinimide (10.7 g, 80.1 mmol)in several portions. The reaction mixture was heated at 80° C. for 16hours, then cooled and concentrated to approximately 100 mL underreduced pressure. The residue was poured into water (1 L), and theresultant precipitate was filtered, washed with water and dried (50° C.under vacuum) to give the title compound as a light brown solid (12.37g, 100%). ¹H NMR (300 MHz, CDCl₃): δ 7.27 (dd, J=7.9, 2.9 Hz, 1H), 7.09(dd, J=7.9, 2.9 Hz, 1H), 4.69 (br s, 2H).

Step 2. 2-Bromo-3-chloro-5-fluorobenzonitrile

To a mixture of 2-amino-3-chloro-5-fluorobenzonitrile (5.0 g, 29 mmol)and copper (II) bromide (7.8 g, 35 mmol) in acetonitrile (130 mL) wasadded t-butyl nitrite (4.2 mL, 35 mmol), drop-wise at 0° C. The reactionmixture was stirred for 2 hours while warming slowly to roomtemperature. The resultant mixture was then concentrated under reducedpressure to approx. half the original volume, and the residue was pouredinto water (1 L) and extracted twice with ethyl acetate. The combinedorganic extracts were washed with water, dried (Na₂SO₄) and evaporated.The crude product was purified by chromatography on silica (20%diethylether in pentane) to give the title compound as a cream colouredsolid (5.4 g, 79%). ¹H NMR (400 MHz, CDCl₃): δ 7.48 (dd, J=7.8, 2.9 Hz,1H), 7.35 (dd, J=7.8, 2.9 Hz, 1H).

Step 3. 3-Chloro-5-fluoro-2-thiazolo[5,4-c]pyridin-2-yl-benzonitrile

A mixture of thiazolo[5,4-c]pyridine (0.5 g, 3.67 mmol),2-bromo-3-chloro-5-fluorobenzonitrile (1.3 g, 5.5 mmol), Pd(PPh₃)₄ (0.42g, 0.36 mmol), copper(I) iodide (70 mg, 0.37 mmol) and cesium carbonate(3.9 g, 12 mmol) in dimethylformamide (15 mL) was heated at 150° C. in amicrowave reactor for 5 minutes. The cooled mixture was poured intowater and extracted twice with ethyl acetate. The combined organicextracts were washed with water, dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by chromatographyon silica (10% diethylether in DCM) to yield a pale solid (0.22 g). Thereaction was repeated on the same scale, and the combined product fromboth reactions was purified by chromatography on silica (5% diethyletherin DCM) to give the title compound as an off-white solid (0.30 g, 14%).¹H NMR (300 MHz, CDCl₃): δ 9.35 (s, 1H), 8.78 (d, J=6.2 Hz, 1H), 8.10(d, J=6.2 Hz, 1H), 7.58 (dd, J=7.8, 2.5 Hz, 1H), 7.53 (dd, J=7.4, 2.5Hz, 1H). LCMS (Method E): RT=2.78, m/z: 290 [M+H⁺].

Step 4.3-Chloro-5-fluoro-2-(5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile

To a solution of3-chloro-5-fluoro-2-thiazolo[5,4-c]pyridin-2-yl-benzonitrile (163 mg,0.56 mmol) in DCM (4 mL) was added methyltrioxorhenium (VII) (15 mg,0.06 mmol) and hydrogen peroxide (27% in water, 0.08 mL, 1.11 mmol). Thereaction mixture was stirred vigorously for 16 hours. Further portionsof methyltrioxorhenium (VII) (5 mg) and hydrogen peroxide (0.04 mL) wereadded and stirring was continued for 5 hours. The resultant mixture wasthen treated with aqueous sodium bicarbonate, the phases were separatedand the aqueous phase was extracted three times with DCM. The combinedorganic washings were dried (Na₂SO₄), filtered and concentrated invacuo. The resultant residue was triturated twice with diethylether anddried (50° C. under vacuum) to yield the title compound as a white solid(154 mg, 90%). ¹H NMR (300 MHz, CDCl₃): δ 8.85 (d, J=1.3 Hz, 1H), 8.36(dd, J=7.0, 1.7 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.59 (dd, J=7.6, 2.7Hz, 1H), 7.55 (dd, J=7.3, 2.7 Hz, 1H). LCMS (Method F): RT=2.34, m/z:306 [M+H⁺].

Step 5.3-Chloro-2-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile

To a suspension of3-chloro-5-fluoro-2-(5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile (154mg, 0.50 mmol) in DCE (2.5 mL) was added phosphorus oxychloride (0.15mL, 1.62 mmol). The resultant mixture was heated at 70° C. After 6hours, a further portion of phosphorus oxychloride (6 drops) was addedand heating was continued for 16 hours. The cooled reaction mixture wastreated with aqueous sodium bicarbonate, the phases were separated andthe aqueous phase was extracted five times with DCM. The combinedorganic washings were dried (Na₂SO₄), filtered and concentrated invacuo. The crude residue was purified by chromatography on silica(10-50% ethyl acetate in cyclohexane) to give the title compound as ayellow solid (118 mg, 73%). ¹H NMR (300 MHz, CDCl₃): δ 8.55 (d, J=5.7Hz, 1H), 8.02 (d, J=5.7 Hz, 1H), 7.59 (dd, J=7.8, 2.5 Hz, 1H), 7.55 (dd,J=7.3, 2.5 Hz, 1H). LCMS (Method D): RT=3.84, m/z: 324 [M+H⁺].

Step 6.2-(4-Bromothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile

To a suspension of3-chloro-2-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile(118 mg, 0.36 mmol) in propionitrile (3.5 mL) was addedbromotrimethylsilane (0.15 mL, 1.1 mmol) and the reaction mixture washeated at 50° C. for 7 hours. The cooled mixture was treated withaqueous sodium bicarbonate and extracted three times with DCM. Thecombined organic washings were dried (Na₂SO₄), filtered and concentratedin vacuo to give the title compound as a yellow solid (133 mg, 100%). ¹HNMR (300 MHz, CDCl₃): δ 8.53 (d, J=5.6 Hz, 1H), 8.04 (d, J=5.6 Hz, 1H),7.59 (dd, J=7.7, 2.5 Hz, 1H), 7.55 (dd, J=7.3, 2.5 Hz, 1H). LCMS (MethodD): RT=3.88, m/z: 368 [M+H⁺].

Step 7.3-Chloro-5-fluoro-2-[4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]benzonitrilehydrochloride

A mixture of2-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile (98mg, 0.26 mmol), (6-aminopyrimidin-4-yl)-methanol (33 mg, 0.26 mmol),Pd₂(dba)₃ (12 mg, 0.013 mmol), XantPhos (15 mg, 0.026 mmol) and cesiumcarbonate (219 mg, 0.67 mmol) in 1,4-dioxane (2 mL) was heated underargon at 80° C. for 16 hours. The cooled reaction mixture was dilutedwith water and extracted five times with ethyl acetate, then three timeswith 10% methanol in DCM. The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified by chromatography on silica (20-100% ethyl acetate incyclohexane) to yield the free base of the title compound (41 mg, 38%).This material was suspended in DCM (2 mL) and 2-propanol (0.5 mL), and asolution of hydrogen chloride in 2-propanol (1.25 N, 1 mL) was added andthe resultant mixture was stirred for 10 minutes. The solvent wasremoved under reduced pressure and the resultant residue was trituratedthree times with diethylether and dried (50° C. under vacuum) to givethe title compound as an off-white solid (44 mg). ¹H NMR (400 MHz,DMSO-d₆): δ 8.93 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.28-8.23 (m, 2H),8.05 (d, J=5.6 Hz, 1H), 7.87 (br s, 1H), 4.64 (s, 2H). LCMS (Method C):RT=3.14, m/z: 413 [M+H⁺].

Additional compounds shown in Table 3 were also made according to theabove procedures.

TABLE 3 LCMS (ESI) Synth. m/z LCMS Ex- Meth- [M + Meth- R_(T) ampleStructure Name od H⁺] od (min) NMR 235

2-[4-(2-Amino-6- methylpyrimidin-4- ylamino)- thiazolo[5,4-c]pyridin-2-yl]-3- chlorobenzonitrile hydrochloride salt 2 394 C 2.88 ¹HNMR (400 MHz, DMSO-d₆): δ 13.12 (br s, 1H), 11.55 (br s, 1H), 8.52 (d, J= 5.6 Hz, 1H), 8.09 (dd, J = 0.9, 7.8 Hz, 1H), 8.04 (dd,J = 1.1, 8.3 Hz,1H), 8.01 (d, J = 5.5 Hz, 1H), 7.08 (t, J = 8.2 Hz, 1H), 6.56 (br s,1H), 2.27 (s, 3H). 236

3-Chloro-2-[4-(6- hydroxymethyl-2- methylpyrimidin-4- ylamino)-thiazolo[5,4- c]pyridin-2-yl]- benzonitrile hydrochloride salt 2 409 C2.85 ¹H NMR (400 MHz, DMSO-d₆): δ 11.91 (br s, 1H), 8.54 (d, J = 5.6 Hz,1H), 8.09 (d, J = 1.0, 7.8 Hz, 1H), 8.05 (dd, J = 1.3, 8.4 Hz, 1H), 8.02(d, J = 5.5 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.58 (br s, 1H), 4.59 (s,2H), 2.56 (s, 3H). 237

3-Chloro-2-[4-(2- hydroxymethyl-2- methylpyrimidin-4- ylamino)-thiazolo[5,4- c]pyridin-2-yl]- benzonitrile hydrochloride salt 2 409 C2.91 ¹H NMR (400 MHz, DMSO-d₆): δ 11.02 (br s, 1H), 8.45 (d, J = 5.6 Hz,1H), 8.09-8.02 (m, 2H), 7.87 (d, J = 5.6 Hz, 1H), 7.80 (t, J = 8.0 Hz,1H), 7.39 (br s, 1H), 4.48 (s, 2H), 2.40 (s, 3H). 238

[2-(4-Amino-2,6- dichlorophenyl)-7- fluorothiazolo[5,4-c]pyridin-4-yl]-(6- methylpyrimidin-4- yl)-amine dihydrochloride salt 2422 C 3.23 ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (br s, 1H), 8.89 (s, 1H),8.52 (d, J = 1.9 Hz, 1H), 7.53 (s, 1H), 6.74 (s, 2H), 2.50 (s, 3H). 239

3-Chloro-5-fluoro- 2-[4-(6- methylpyrimidin-4- ylamino)- thiazolo[5,4-c]pyridin-2- yl]benzonitrile 2 397 C 3.26 ¹H NMR (400 MHz, DMSO-d₆): δ10.70 (s, 1H), 8.59 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.21- 8.15 (m,2H), 7.82 (d, J = 5.8 Hz, 1H), 7.52 (s, 1H), 2.35 (s, 3H). 240

2-[4-(6-Amino-2- methylpyrimidin-4- ylamino)- thiazolo[5,4-c]pyridin-2-yl]-3- chloro-5- fluorobenzonitrile hydrochloride 2 412 C3.08 ¹H NMR (400 MHz, DMSO-d₆): δ 11.34 (br s, 1H), 8.49 (d, J = 5.6 Hz,1H), 8.24-8.17 (m, 2H), 7.92 (d, J = 5.6 Hz, 1H), 7.09 (br s, 1H), 2.50(s, 3H).

Specific reference is made to U.S. Provisional Patent Application Ser.No. 61/383,273, filed Sep. 15, 2010, which is incorporated herein byreference in its entirety for all purposes. Although the invention hasbeen described and illustrated with a certain degree of particularity,it is understood that the present disclosure has been made only by wayof example, and that numerous changes in the combination and arrangementof parts can be resorted to by those skilled in the art withoutdeparting from the spirit and scope of the invention, as defined by theclaims.

What is claimed is:
 1. A compound of Formula I:

stereoisomers, tautomers, solvates, prodrugs and pharmaceuticallyacceptable salts thereof, wherein: A is CR³ or N; X is CR¹⁵ or N; R¹ isindependently hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, —CF₃, —OR⁶, —SR⁶, —OCF₃, —CN, —NO₂, —C(O)R⁶,—C(O)OR⁶, —C(O)NR⁶R⁷, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶R⁷, —NR⁶S(O)₁₋₂R⁷,—NR⁶SO₂NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁷, —NR⁶C(O)NR⁶R⁷, —OC(O)NR⁶R⁷ or—NR⁶R⁷, wherein both R¹ cannot be hydrogen at the same time, and whereinsaid alkyl, alkenyl, alkynyl and cycloalkyl are optionally substitutedby halogen, oxo, —CN, OR⁶, —NR⁶R⁷, C₃-C₆ cycloalkyl, 3-6 memberedheterocyclyl or phenyl and said cycloalkyl, heterocyclyl and phenyl areindependently optionally substituted by R¹⁰; R² and R³ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR⁸, —(C₀-C₃alkylene)SR⁸, —(C₀-C₃ alkylene)NR⁸R⁹, —(C₀-C₃ alkylene)CF₃, —O(C₀-C₃alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —(C₀-C₃ alkylene)C(O)R⁸, —(C₀-C₃alkylene)C(O)OR⁸, —(C₀-C₃ alkylene)C(O)NR⁸R⁹, —(C₀-C₃alkylene)NR⁸C(O)R⁹, —(C₀-C₃ alkylene)S(O)₁₋₂R⁸, —(C₀-C₃alkylene)NR⁸S(O)₁₋₂R⁹, —(C₀-C₃ alkylene)S(O)₁₋₂NR⁸R⁹, —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃alkylene)phenyl, wherein R² and R³ are each independently optionallysubstituted by R¹⁰; R⁴ is hydrogen, —NR⁶—, —NR⁶R⁷, —NR⁶C(O)—,—NR⁶C(O)O—, —NR⁶C(O)NR⁷—, NR⁶S(O)₁₋₂— or —NR⁶S(O)₁₋₂NR⁷—; R⁵ is absent,hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl,C₆-C₁₀ aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl,wherein R⁵ is optionally substituted by R¹⁰; R⁶ and R⁷ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₃-C₆ cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkylare independently optionally substituted by halogen, C₁-C₆ alkyl, oxo,—CN, —OR¹¹ or —NR¹¹R¹²; or R⁶ and R⁷ are independently taken togetherwith the atom to which they are attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹² orC₁-C₆ alkyl optionally substituted by halogen; R⁸ and R⁹ are eachindependently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl,3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein saidalkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independentlyoptionally substituted by R¹⁰; or R⁸ and R⁹ are independently takentogether with the atom to which they are attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —NR¹¹R¹² or C₁-C₆alkyl; R¹⁰ is independently hydrogen, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹¹,—(C₀-C₃ alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹², —(C₀-C₃ alkylene)CF₃,—(C₀-C₃ alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃ alkylene)C(O)R¹¹, —(C₀-C₃alkylene)C(O)OR¹¹, —(C₀-C₃ alkylene)C(O)NR¹¹R¹², —(C₀-C₃alkylene)NR¹¹C(O)R¹², —(C₀-C₃ alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃ alkylene)S(O)₁₋₂NR¹¹R¹², —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)C(O)(3-10-membered heterocyclyl),—(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,wherein R¹⁰ is independently optionally substituted by halogen, oxo,—CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃ alkylene)NR¹³R¹⁴, —(C₀-C₃alkylene)C(O)R¹³, —(C₀-C₃ alkylene)S(O)₁₋₂R¹³ or C₁-C₆ alkyl optionallysubstituted by oxo, —CN or halogen; R¹¹ and R¹² are each independentlyhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl andheterocyclyl are independently optionally substituted by halogen, oxo,—CN, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted by halogen,—CN or oxo; or R¹¹ and R¹² are taken together with the atom to whichthey attached to form a 3-6 membered heterocyclyl optionally substitutedby halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substitutedby halogen, oxo or OH; R¹³ and R¹⁴ are each independently hydrogen orC₁-C₆ alkyl optionally substituted by halogen or oxo; or R¹³ and R¹⁴ aretaken together with the atom to which they attached to form a 3-6membered heterocyclyl optionally substituted by halogen, oxo or C₁-C₆alkyl optionally substituted by halogen or oxo; R¹⁵ is hydrogen,halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(C₀-C₃ alkylene)CN,—(C₀-C₃ alkylene)OR¹⁸, —(C₀-C₃ alkylene)SR¹⁸, —(C₀-C₃ alkylene)NR¹⁸R¹⁹,—(C₀-C₃ alkylene)CF₃, —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂,—(C₀-C₃ alkylene)C(O)R¹⁸, —(C₀-C₃ alkylene)C(O)OR¹⁸, —(C₀-C₃alkylene)C(O)NR¹⁸R¹⁹, —(C₀-C₃ alkylene)NR¹⁸C(O)R¹⁹, —(C₀-C₃alkylene)S(O)₁₋₂R¹⁸, —(C₀-C₃ alkylene)NR¹⁸S(O)₁₋₂R¹⁹, —(C₀-C₃alkylene)S(O)₁₋₂NR¹⁸R¹⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)(3-6-membered heterocyclyl), —(C₀-C₃ alkylene)(5-6-memberedheteroaryl) or —(C₀-C₃ alkylene)phenyl; R¹⁶ and R¹⁷ are eachindependently hydrogen or C₁-C₆ alkyl optionally substituted by halogenor oxo; or R¹⁶ and R¹⁷ are taken together with the atom to which theyattached to form a 3-6 membered heterocyclyl optionally substituted byhalogen, oxo or C₁-C₆ alkyl optionally substituted by oxo or halogen;and R¹⁸ and R¹⁹ are each independently hydrogen or C₁-C₆ alkyloptionally substituted by halogen or oxo; other than2-(2-chlorophenyl)thiazolo[5,4-c]pyridine,2-(thiazolo[5,4-c]pyridin-2-yl)aniline,2-phenoxy-N-(2-thiazolo[5,4-c]pyridin-2-yl-phenyl)-propanamide,N-(2-thiazolo[5,4-c]pyridin-2-ylphenyl)-benzenepropanamide,2-(2-methylphenyl)-thiazolo[5,4-c]pyridine,2-[2-methoxy-4-(methylthio)phenyl]-thiazolo[5,4-c]pyridine and2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine.
 2. The compound of claim1, wherein A is CR³ and X is CR⁵.
 3. The compound of claim 2, whereinone R¹ is halogen and the other R¹ is hydrogen, halogen, C₁-C₃ alkyl,C₃-C₄ cycloalkyl, —CF₃, —OH, —O(C₁-C₃ alkyl), —SH, —S(C₁-C₃ alkyl),—OCF₃, —CN, —NO₂, —NHSO₂CH₃, —NHC(O)R⁷ or —NR⁶R⁷, wherein said alkyl andcycloalkyl are optionally substituted by halogen, OR⁶, —NR⁶R⁷ or phenyl.4. The compound of claim 3, wherein R¹ is Cl.
 5. The compound of claim1, wherein R² is hydrogen.
 6. The compound of claim 1, wherein R³ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN,—NR⁸R⁹, —NR C(O)R⁹, —C(O)R⁸ or —S(O)₁₋₂(C₁-C₃ alkyl), wherein saidalkyl, alkenyl and alkynyl are independently optionally substituted byhalogen, oxo, —OR¹¹ or —NR¹¹R¹².
 7. The compound of claim 6, wherein R³is hydrogen or —CN.
 8. The compound of claim 1, wherein the portion ofFormula I having the structure:

is selected from:

wherein the wavy lines represent the point of attachment in Formula I.9. The compound of claim 1, wherein R⁴ is hydrogen, —NR⁶—, —NR⁶C(O)—,—NR⁶C(O)O— or —NR⁶C(O)NR⁷—.
 10. The compound of claim 1, wherein R⁵ isC₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, phenyl, 3-10-membered heterocyclyl or5-10-membered heteroaryl, wherein R⁵ is optionally substituted by R¹⁰.11. The compound of claim 10, wherein R⁵ is selected from methyl, ethyl,isopropyl, tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂NH₂, —CH₂N(CH₃)₂or —CH₂CH₂NH₂ phenyl,

wherein the wavy line represents the point of attachment of R⁵ inFormula I.
 12. The compound of claim 1, wherein R¹⁰ is selected from F,—CN, methyl, ethyl, isopropy, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₂OH,—C(CH₃)₂OH, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —OH, —OCH₃, —NH₂,—NHCH₃, —NHC(O)CH₃, —N(CH₃)₂, —N(CH₂CH₂OH)₂, —NHCH₂CH₂OH,—N(CH₃)CH₂CH₂OH, —NHCH₂C(CH₃)₂OH, —N(CH₃)CH₂C(CH₃)₂OH, —C(O)NH₂,—C(O)NHCH₃, —C(O)N(CH₃)₂, —CH₂thiomorpholinyl dioxide, —CH₂-morpholinyl,—CH₂cyclopropyl, —CH(OH)CH₃, —CH(NH₂)CH₃, (R)—CH(OH)CH₃, (R)—CH(NH₂)CH₃,(S)—CH(OH)CH₃, (S)—CH(NH₂)CH₃,

wherein the wavy line represents the point of attachment in Formula I.13. A pharmaceutical composition comprising a compound of Formula I

stereoisomers, tautomers, solvates, prodrugs or pharmaceuticallyacceptable salts thereof, wherein: A is CR³ or N; X is CR¹⁵ or N; R¹ isindependently hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, —CF₃, —OR⁶, —SR⁶, —OCF₃, —CN, —NO₂, —C(O)R⁶,—C(O)OR⁶, —C(O)NR⁶R⁷, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶R⁷, —NR⁶S(O)₁₋₂R⁷,—NR⁶SO₂NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁷, —NR⁶C(O)NR⁶R⁷, —OC(O)NR⁶R⁷ or—NR⁶R⁷, wherein both R¹ cannot be hydrogen at the same time, and whereinsaid alkyl, alkenyl, alkynyl and cycloalkyl are optionally substitutedby halogen, oxo, —CN, OR⁶, —NR⁶R⁷, C₃-C₆ cycloalkyl, 3-6 memberedheterocyclyl or phenyl and said cycloalkyl, heterocyclyl and phenyl areindependently optionally substituted by R¹⁰; R² and R³ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR⁸, —(C₀-C₃alkylene)SR⁸, —(C₀-C₃ alkylene)NR⁸R⁹, —(C₀-C₃ alkylene)CF₃, —O(C₀-C₃alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —(C₀-C₃ alkylene)C(O)R⁸, —(C₀-C₃alkylene)C(O)OR⁸, —(C₀-C₃ alkylene)C(O)NR⁸R⁹, —(C₀-C₃alkylene)NR⁸C(O)R⁹, —(C₀-C₃ alkylene)S(O)₁₋₂R⁸, —(C₀-C₃alkylene)NR⁸S(O)₁₋₂R⁹, —(C₀-C₃ alkylene)S(O)₁₋₂NR⁸R⁹, —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃alkylene)phenyl, wherein R² and R³ are each independently optionallysubstituted by R¹⁰; R⁴ is hydrogen, —NR⁶—, —NR⁶R⁷, —NR⁶C(O)—,—NR⁶C(O)O—, —NR⁶C(O)NR⁷—, —NR⁶S(O)₁₋₂— or —NR⁶S(O)₁₋₂NR⁷—; R⁵ is absent,hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl,C₆-C₁₀ aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl,wherein R⁵ is optionally substituted by R¹⁰; R⁶ and R⁷ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₃-C₆ cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkylare independently optionally substituted by halogen, C₁-C₆ alkyl, oxo,—CN, —OR¹¹ or —NR¹¹R¹²; or R⁶ and R⁷ are independently taken togetherwith the atom to which they are attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹² orC₁-C₆ alkyl optionally substituted by halogen; R⁸ and R⁹ are eachindependently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl,3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein saidalkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independentlyoptionally substituted by R¹⁰; or R⁸ and R⁹ are independently takentogether with the atom to which they are attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —NR¹¹R¹² or C₁-C₆alkyl; R¹⁰ is independently hydrogen, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹¹,—(C₀-C₃ alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹², —(C₀-C₃ alkylene)CF₃,—(C₀-C₃ alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃ alkylene)C(O)R¹¹, —(C₀-C₃alkylene)C(O)OR¹¹, —(C₀-C₃ alkylene)C(O)NR¹¹R¹², —(C₀-C₃alkylene)NR¹¹C(O)R¹², —(C₀-C₃ alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃ alkylene)S(O)₁₋₂NR¹¹R¹², —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)C(O)(3-10-membered heterocyclyl),—(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,wherein R¹⁰ is independently optionally substituted by halogen, oxo,—CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃ alkylene)NR¹³R¹⁴, —(C₀-C₃alkylene)C(O)R¹³, —(C₀-C₃ alkylene)S(O)₁₋₂R¹³ or C₁-C₆ alkyl optionallysubstituted by oxo, —CN or halogen; R¹¹ and R¹² are each independentlyhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl andheterocyclyl are independently optionally substituted by halogen, oxo,—CN, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted by halogen,—CN or oxo; or R¹¹ and R¹² are taken together with the atom to whichthey attached to form a 3-6 membered heterocyclyl optionally substitutedby halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substitutedby halogen, oxo or OH; R¹³ and R¹⁴ are each independently hydrogen orC₁-C₆ alkyl optionally substituted by halogen or oxo; or R¹³ and R¹⁴ aretaken together with the atom to which they attached to form a 3-6membered heterocyclyl optionally substituted by halogen, oxo or C₁-C₆alkyl optionally substituted by halogen or oxo; R¹⁵ is hydrogen,halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(C₀-C₃ alkylene)CN,—(C₀-C₃ alkylene)OR¹⁸, —(C₀-C₃ alkylene)SR¹⁸, —(C₀-C₃ alkylene)NR¹⁸R¹⁹,—(C₀-C₃ alkylene)CF₃, —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂,—(C₀-C₃ alkylene)C(O)R¹⁸, —(C₀-C₃ alkylene)C(O)OR¹⁸, —(C₀-C₃alkylene)C(O)NR¹⁸R¹⁹, —(C₀-C₃ alkylene)NR¹⁸C(O)R¹⁹, —(C₀-C₃alkylene)S(O)₁₋₂R¹⁸, —(C₀-C₃ alkylene)NR¹⁸S(O)₁₋₂R¹⁹, —(C₀-C₃alkylene)S(O)₁₋₂NR¹⁸R¹⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)(3-6-membered heterocyclyl), —(C₀-C₃ alkylene)(5-6-memberedheteroaryl) or —(C₀-C₃ alkylene)phenyl; R¹⁶ and R¹⁷ are eachindependently hydrogen or C₁-C₆ alkyl optionally substituted by halogenor oxo; or R¹⁶ and R¹⁷ are taken together with the atom to which theyattached to form a 3-6 membered heterocyclyl optionally substituted byhalogen, oxo or C₁-C₆ alkyl optionally substituted by oxo or halogen;and R¹⁸ and R¹⁹ are each independently hydrogen or C₁-C₆ alkyloptionally substituted by halogen or oxo.
 14. The composition of claim13, further comprising a pharmaceutically acceptable carrier, adjuvantor vehicle.
 15. A method of treating a disease responsive to theinhibition of TYK2 kinase activity in a patient, comprisingadministering to the patient a therapeutically effective amount of acomposition of claim
 13. 16. The method of claim 15, wherein saiddisease is an inflammatory disease.
 17. The method of claim 16, whereinsaid disease is asthma, inflammatory bowel disease, Crohn's disease,ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis,atopic dermatitis, contact dermatitis, delayed hypersensitivityreactions, lupus or multiple sclerosis.
 18. The method of claim 15,further comprising administering a second therapeutic agent.
 19. Amethod of manufacturing a compound of claim 1, comprising: (a) reactinga compound of formula (I):

wherein Lv is a leaving group, with a compound of the formula H—R⁴—R⁵under conditions sufficient to form a compound of Formula I.
 20. Acompound of formula (i)

wherein Lv is a leaving group; A is CR³ or N; X is CR¹⁵ or N; R¹ isindependently hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, —CF₃, —OR⁶, —SR⁶, —OCF₃, —CN, —NO₂, —C(O)R⁶,—C(O)OR⁶, —C(O)NR⁶R⁷, —S(O)₁₋₂R⁶, —S(O)₁₋₂NR⁶R⁷, —NR⁶S(O)₁₋₂R⁷,—NR⁶SO₂NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁷, —NR⁶C(O)NR⁶R⁷, —OC(O)NR⁶R⁷ or—NR⁶R⁷, wherein both R¹ cannot be hydrogen at the same time, and whereinsaid alkyl, alkenyl, alkynyl and cycloalkyl are optionally substitutedby halogen, oxo, —CN, OR⁶, —NR⁶R⁷, C₃-C₆ cycloalkyl, 3-6 memberedheterocyclyl or phenyl and said cycloalkyl, heterocyclyl and phenyl areindependently optionally substituted by R¹⁰; R² and R³ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR⁸, —(C₀-C₃alkylene)SR⁸, —(C₀-C₃ alkylene)NR⁸R⁹, —(C₀-C₃ alkylene)CF₃, —O(C₀-C₃alkylene)CF₃, —(C₀-C₃ alkylene)NO₂, —(C₀-C₃ alkylene)C(O)R⁸, —(C₀-C₃alkylene)C(O)OR⁸, —(C₀-C₃ alkylene)C(O)NR⁸R⁹, —(C₀-C₃alkylene)NR⁸C(O)R⁹, —(C₀-C₃ alkylene)S(O)₁₋₂R⁸, —(C₀-C₃alkylene)NR⁸S(O)₁₋₂R⁹, —(C₀-C₃ alkylene)S(O)₁₋₂NR⁸R⁹, —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃alkylene)phenyl, wherein R² and R³ are each independently optionallysubstituted by R¹⁰; R⁴ is hydrogen, —NR⁶—, —NR⁶R⁷, —NR⁶C(O)—,—NR⁶C(O)O—, —NR⁶C(O)NR⁷—, NR⁶S(O)₁₋₂— or —NR⁶S(O)₁₋₂NR⁷—; R⁵ is absent,hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl,C₆-C₁₀ aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl,wherein R⁵ is optionally substituted by R¹⁰; R⁶ and R⁷ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₃-C₆ cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkylare independently optionally substituted by halogen, C₁-C₆ alkyl, oxo,—CN, —OR¹¹ or —NR¹¹R¹²; or R⁶ and R⁷ are independently taken togetherwith the atom to which they are attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹² orC₁-C₆ alkyl optionally substituted by halogen; R⁸ and R⁹ are eachindependently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl,3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein saidalkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independentlyoptionally substituted by R¹⁰; or R⁸ and R⁹ are independently takentogether with the atom to which they are attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —NR¹¹R¹² or C₁-C₆alkyl; R¹⁰ is independently hydrogen, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —(C₀-C₃ alkylene)CN, —(C₀-C₃ alkylene)OR¹¹,—(C₀-C₃ alkylene)SR¹¹, —(C₀-C₃ alkylene)NR¹¹R¹², —(C₀-C₃ alkylene)CF₃,—(C₀-C₃ alkylene)NO₂, —C═NH(OR¹¹), —(C₀-C₃ alkylene)C(O)R¹¹, —(C₀-C₃alkylene)C(O)OR¹¹, —(C₀-C₃ alkylene)C(O)NR¹¹R¹², —(C₀-C₃alkylene)NR¹¹C(O)R¹², —(C₀-C₃ alkylene)S(O)₁₋₂R¹¹, —(C₀-C₃alkylene)NR¹¹S(O)₁₋₂R¹², —(C₀-C₃ alkylene)S(O)₁₋₂NR¹¹R¹², —(C₀-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃ alkylene)(3-10-memberedheterocyclyl), —(C₀-C₃ alkylene)C(O)(3-10-membered heterocyclyl),—(C₀-C₃ alkylene)(5-10-membered heteroaryl) or —(C₀-C₃ alkylene)phenyl,wherein R¹⁰ is independently optionally substituted by halogen, oxo,—CF₃, —(C₀-C₃ alkylene)OR¹³, —(C₀-C₃ alkylene)NR¹³R¹⁴, —(C₀-C₃alkylene)C(O)R³, —(C₀-C₃ alkylene)S(O)₁₋₂R¹³ or C₁-C₆ alkyl optionallysubstituted by oxo, —CN or halogen; R¹¹ and R¹² are each independentlyhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl andheterocyclyl are independently optionally substituted by halogen, oxo,—CN, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted by halogen,—CN or oxo; or R¹¹ and R¹² are taken together with the atom to whichthey attached to form a 3-6 membered heterocyclyl optionally substitutedby halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substitutedby halogen, oxo or OH; R¹³ and R¹⁴ are each independently hydrogen orC₁-C₆ alkyl optionally substituted by halogen or oxo; or R¹³ and R¹⁴ aretaken together with the atom to which they attached to form a 3-6membered heterocyclyl optionally substituted by halogen, oxo or C₁-C₆alkyl optionally substituted by halogen or oxo; R¹⁵ is hydrogen,halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(C₀-C₃ alkylene)CN,—(C₀-C₃ alkylene)OR¹⁸, —(C₀-C₃ alkylene)SR¹⁸, —(C₀-C₃ alkylene)NR¹⁸R¹⁹,—(C₀-C₃ alkylene)CF₃, —O(C₀-C₃ alkylene)CF₃, —(C₀-C₃ alkylene)NO₂,—(C₀-C₃ alkylene)C(O)R¹⁸, —(C₀-C₃ alkylene)C(O)OR¹⁸, —(C₀-C₃alkylene)C(O)NR¹⁸R¹⁹, —(C₀-C₃ alkylene)NR¹⁸C(O)R¹⁹, —(C₀-C₃alkylene)S(O)₁₋₂R¹⁸, —(C₀-C₃ alkylene)NR¹⁸S(O)₁₋₂R¹⁹, —(C₀-C₃alkylene)S(O)₁₋₂NR¹⁸R¹⁹, —(C₀-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₀-C₃alkylene)(3-6-membered heterocyclyl), —(C₀-C₃ alkylene)(5-6-memberedheteroaryl) or —(C₀-C₃ alkylene)phenyl; R¹⁶ and R¹⁷ are eachindependently hydrogen or C₁-C₆ alkyl optionally substituted by halogenor oxo; or R¹⁶ and R¹⁷ are taken together with the atom to which theyattached to form a 3-6 membered heterocyclyl optionally substituted byhalogen, oxo or C₁-C₆ alkyl optionally substituted by oxo or halogen;and R¹⁸ and R¹⁹ are each independently hydrogen or C₁-C₆ alkyloptionally substituted by halogen or oxo; other than4-chloro-2-(2,3-difluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,3-dimethylphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-methoxyphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-o-tolylthiazolo[5,4-c]pyridine,4-chloro-2-(2-(difluoromethoxy)phenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-fluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,3-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,4-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,4-dimethylphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-chlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,6-dimethylphenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,5-dichlorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine,2-(2-bromophenyl)-4-chlorothiazolo[5,4-c]pyridine,4-chloro-2-(2,6-difluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,5-difluorophenyl)thiazolo[5,4-c]pyridine,4-chloro-2-(2,4-difluorophenyl)thiazolo[5,4-c]pyridine or4-chloro-2-(2,5-dimethyl)thiazolo[5,4-c]pyridine.
 21. The compound ofclaim 20, wherein -Lv is a halogen, —OR or —OS(O)₁₋₂R, wherein R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl orheterocyclyl and R is independently optionally substituted.
 22. Thecompound of claim 21, wherein -Lv is a halogen.
 23. A kit comprising apharmaceutical composition of claim 13 and instructions for use.